text: representative compounds of the present invention exhibit high selectivity for the human alpha 1a adrenergic receptor . one implication of this selectivity is that these compounds display selectivity for lowering intraurethral pressure without substantially affecting diastolic blood pressure . representative compounds utilized in the methods of this invention display submicromolar affinity for the human alpha 1a adrenergic receptor subtype while displaying at least five - fold lower affinity for the human alpha 1d and alpha 1b adrenergic receptor subtypes , and many other g - protein coupled human receptors . preferred compounds of this invention exhibit nanomolar affinity for the human alpha 1a adrenergic receptor subtype while displaying at least 10 fold lower affinity for the human alpha 1d and alpha 1b adrenergic receptor subtypes , opioid receptors and many other g - protein coupled human receptors . these compounds are administered in dosages effective to antagonize the alpha 1a receptor where such treatment is needed , as in bph . for use in medicine , the salts of the compounds of this invention refer to non - toxic &# 34 ; pharmaceutically acceptable salts .&# 34 ; other salts may , however , be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts . suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may , for example , be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid , sulphuric acid , fumaric acid , maleic acid , succinic acid , acetic acid , benzoic acid , oxalic acid , citric acid , tartaric acid , carbonic acid or phosphoric acid . furthermore , where the compounds of the invention carry an acidic moiety , suitable pharmaceutically acceptable salts thereof may include alkali metal salts , e . g . sodium or potassium salts ; alkaline earth metal salts , e . g . calcium or magnesium salts ; and salts formed with suitable organic ligands , e . g . quaternary ammonium salts . thus , representative pharmaceutically acceptable salts include the following : acetate , benzenesulfonate , benzoate , bicarbonate , bisulfate , bitartrate , borate , bromide , calcium , camsylate , carbonate , chloride , clavulanate , citrate , dihydrochloride , edetate , edisylate , estolate , esylate , fumarate , gluceptate , gluconate , glutamate , glycollylarsanilate , hexylresorcinate , hydrabamine , hydrobromide , hydrochloride , hydroxynaphthoate , iodide , isothionate , lactate , lactobionate , laurate , malate , maleate , mandelate , mesylate , methylbromide , methylnitrate , methylsulfate , mucate , napsylate , nitrate , n - methylglucamine ammonium salt , oleate , oxalate , pamoate ( embonate ), palmitate , pantothenate , phosphate / diphosphate , polygalacturonate , salicylate , stearate , sulfate , subacetate , succinate , tannate , tartrate , teoclate , tosylate , triethiodide and valerate . the present invention includes within its scope prodrugs of the compounds of this invention . in general , such prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound . conventional procedures for the selection and preparation of suitable prodrug derivatives are described , for example , in &# 34 ; design of prodrugs ,&# 34 ; ed . h . bundgaard , elsevier , 1985 . metabolites of these compounds include active species produced upon introduction of compounds of this invention into the biological milieu . where the compounds according to the invention have at least one chiral center , they may accordingly exist as enantiomers . where the compounds according to the invention possess two or more chiral centers , they may additionally exist as diastereoisomers . it is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention . furthermore , some of the crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention . in addition , some of the compounds of the present invention may form solvates with water ( i . e ., hydrates ) or common organic solvents . such solvates are also encompassed within the scope of this invention . the term &# 34 ; alkyl &# 34 ; shall mean straight or branched chain alkanes of one to ten total carbon atoms , or any number within this range ( i . e ., methyl , ethyl , 1 - propyl , 2 - propyl , n - butyl , s - butyl , t - butyl , etc .). the term &# 34 ; alkenyl &# 34 ; shall mean straight or branched chain alkenes of two to ten total carbon atoms , or any number within this range . the term &# 34 ; aryl &# 34 ; as used herein , except where otherwise specifically defined , refers to unsubstituted , mono - or poly - substituted aromatic groups such as phenyl or naphthyl . the term &# 34 ; cycloalkyl &# 34 ; shall mean cyclic rings of alkanes of three to eight total carbon atoms ( i . e ., cyclopropyl , cyclobutyl , cyclopentyl , cyclohexyl , cycloheptyl or cyclooctyl ). whenever the term &# 34 ; alkyl &# 34 ; or &# 34 ; aryl &# 34 ; or either of their prefix roots appear in a name of a substituent ( e . g ., aralkoxyaryloxy ) it shall be interpreted as including those limitations given above for &# 34 ; alkyl &# 34 ; and &# 34 ; aryl .&# 34 ; designated numbers of carbon atoms ( e . g ., c 1 - 10 ) shall refer independently to the number of carbon atoms in an alkyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root . the term &# 34 ; substituted &# 34 ; shall be deemed to include multiple degrees of substitution by a named substitutent . the term &# 34 ; poly - substituted &# 34 ; as used herein shall include di -, tri -, tetra - and penta - substitution by a named substituent . where multiple substituent moieties are disclosed or claimed , the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties , singly or plurally . the term heterocycle or heterocyclic ring , as used herein , represents an unsubstituted or substituted stable 5 - to 7 - membered monocyclic ring system which may be saturated or unsaturated , and which consists of carbon atoms and from one to three heteroatoms selected from n , o or s , and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized , and the nitrogen heteroatom may optionally be quaternized . the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure . examples of such heterocyclic groups include , but is not limited to , piperidinyl , piperazinyl , oxopiperazinyl , oxopiperidinyl , oxopyrrolidinyl , oxoazepinyl , azepinyl , pyrrolyl , pyrrolidinyl , furanyl , thienyl , pyrazolyl , pyrazolidinyl , imidazolyl , imidazolinyl , imidazolidinyl , pyridyl , pyrazinyl , pyrimidinyl , pyridazinyl , oxazolyl , oxazolidinyl , isooxazolyl , isoxazolidinyl , morpholinyl , thiazolyl , thiazolidinyl , isothiazolyl , thiadiazolyl , tetrahydropyranyl , thiamorpholinyl , thiamorpholinyl sulfoxide , thiamorpholinyl sulfone , and oxadiazolyl . morpholino is the same as morpholinyl . the term &# 34 ; subject ,&# 34 ; as used herein refers to an animal , preferably a mammal , most preferably a human , who has been the object of treatment , observation or experiment . the term &# 34 ; therapeutically effective amount &# 34 ; as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue , system , animal or human that is being sought by a researcher , veterinarian , medical doctor or other clinician , which includes alleviation of the symptoms of the disease being treated . the present invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier . preferably these compositions are in unit dosage forms such as tablets , pills , capsules , powders , granules , sterile parenteral solutions or suspensions , metered aerosol or liquid sprays , drops , ampoules , auto - injector devices or suppositories ; for oral , parenteral , intranasal , sublingual or rectal administration , or for administration by inhalation or insufflation . alternatively , the compositions may be presented in a form suitable for once - weekly or once - monthly administration ; for example , an insoluble salt of the active compound , such as the decanoate salt , may be adapted to provide a depot preparation for intramuscular injection . for preparing solid compositions such as tablets , the principal active ingredient is mixed with a pharmaceutical carrier , e . g . conventional tableting ingredients such as corn starch , lactose , sucrose , sorbitol , talc , stearic acid , magnesium stearate , dicalcium phosphate or gums , and other pharmaceutical diluents , e . g . water , to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention , or a pharmaceutically acceptable salt thereof . when referring to these preformulation compositions as homogeneous , it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets , pills and capsules . this solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0 . 1 to about 500 mg of the active ingredient of the present invention . the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action . for example , the tablet or pill can comprise an inner dosage and an outer dosage component , the latter being in the form of an envelope over the former . the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release . a variety of materials can be used for such enteric layers or coatings , such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac , cetyl alcohol and cellulose acetate . the liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions , suitably flavoured syrups , aqueous or oil suspensions , and flavoured emulsions with edible oils such as cottonseed oil , sesame oil , coconut oil or peanut oil , as well as elixirs and similar pharmaceutical vehicles . suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth , acacia , alginate , dextran , sodium carboxymethylcellulose , methylcellulose , polyvinyl - pyrrolidone or gelatin . where the processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers , these isomers may be separated by conventional techniques such as preparative chromatography . the compounds may be prepared in racemic form , or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution . the compounds may , for example , be resolved into their component enantiomers by standard techniques , such as the formation of diastereomeric pairs by salt formation with an optically active acid , such as (-)- di - p - toluoyl - d - tartaric acid and / or (+)- di - p - toluoyl - 1 - tartaric acid followed by fractional crystallization and regeneration of the free base . the compounds may also be resolved by formation of diastereomeric esters or amides , followed by chromatographic separation and removal of the chiral auxiliary . alternatively , the compounds may be resolved using a chiral hplc column . during any of the processes for preparation of the compounds of the present invention , it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned . this may be achieved by means of conventional protecting groups , such as those described in protective groups in organic chemistry , ed . j . f . w . mcomie , plenum press , 1973 ; and t . w . greene & amp ; p . g . m . wuts , protective groups in organic synthesis , john wiley & amp ; sons , 1991 . the protecting groups may be removed at a convenient subsequent stage using methods known from the art . the specificity of binding of compounds showing affinity for the alpha 1a receptor is shown by comparing affinity to membranes obtained from tranfected cell lines that express the alpha 1a receptor and membranes from cell lines or tissues known to express other types of alpha ( e . g ., alpha 1d , alpha 1b ) or beta adrenergic receptors . expression of the cloned human alpha 1d , alpha 1b , and alpha 1a receptors and comparison of their binding properties with known selective antagonists provides a rational way for selection of compounds and discovery of new compounds with predictable pharmacological activities . antagonism by these compounds of the human alpha 1a adrenergic receptor subtype may be functionally demonstrated in anesthetized animals . these compounds may be used to increase urine flow without exhibiting orthostatic hypotensive effects . the ability of compounds of the present invention to specifically bind to the alpha 1a receptor makes them useful for the treatment of bph . the specificity of binding of compounds showing affinity for the alpha 1a receptor is compared against the binding affinities to other types of alpha or beta adrenergic receptors . the human alpha adrenergic receptor of the 1a subtype was recently identified , cloned and expressed as described in pct international application publication nos . w094 / 08040 , published apr . 14 , 1994 and wo 94 / 21660 , published sep . 14 , 1994 , each of which is hereby incorporated by reference . the cloned human alpha 1a receptor , when expressed in mammalian cell lines , is used to discover ligands that bind to the receptor and alter its function . expression of the cloned human alpha 1d , alpha 1b , and alpha 1a receptors and comparison of their binding properties with known selective antagonists provides a rational way for selection of compounds and discovery of new compounds with predictable pharmacological activities . compounds of this invention exhibiting selective human alpha 1a adrenergic receptor antagonism may further be defined by counterscreening . this is accomplished according to methods known in the art using other receptors responsible for mediating diverse biological functions . see e . g ., pct international application publication no . w094 / 10989 , published may 26 , 1994 ; u . s . pat . no . 5 , 403 , 847 , issued apr . 4 , 1995 , the contents of which are hereby incorporated by reference !. compounds which are both selective amongst the various human alpha 1 adrenergic receptor subtypes and which have low affinity for other receptors , such as the alpha2 adrenergic receptors , the β - adrenergic receptors , the muscarinic receptors , the serotonin receptors , and others are particularly preferred . the absence of these non - specific activities may be confirmed by using cloned and expressed receptors in an analogous fashion to the method disclosed herein for identifying compounds which have high affinity for the various human alpha 1 adrenergic receptors . furthermore , functional biological tests are used to confirm the effects of identified compounds as alpha 1 a adrenergic receptor antagonists . the present invention also has the objective of providing suitable topical , oral , systemic and parenteral pharmaceutical formulations for use in the novel methods of treatment of the present invention . the compositions containing compounds of this invention as the active ingredient for use in the specific antagonism of human alpha 1a adrenergic receptors can be administered in a wide variety of therapeutic dosage forms in conventional vehicles for systemic administration . for example , the compounds can be administered in such oral dosage forms as tablets , capsules ( each including timed release and sustained release formulations ), pills , powders , granules , elixirs , tinctures , solutions , suspensions , syrups and emulsions , or by injection . likewise , they may also be administered in intravenous ( both bolus and infusion ), intraperitoneal , subcutaneous , topical with or without occlusion , or intramuscular form , all using forms well known to those of ordinary skill in the pharmaceutical arts . an effective but non - toxic amount of the compound desired can be employed as an alpha 1a antagonistic agent . advantageously , compounds of the present invention may be administered in a single daily dose , or the total daily dosage may be administered in divided doses of two , three or four times daily . furthermore , compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles , or via transdermal routes , using those forms of transdermal skin patches well known to those of ordinary skill in that art . to be administered in the form of a transdermal delivery system , the dosage administration will , of course , be continuous rather than intermittent throughout the dosage regimen . the dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type , species , age , weight , sex and medical condition of the patient ; the severity of the condition to be treated ; the route of administration ; the renal and hepatic function of the patient ; and the particular compound thereof employed . a physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent , counter or arrest the progress of the condition . optimal precision in achieving concentration of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug &# 39 ; s availability to target sites . this involves a consideration of the distribution , equilibrium , and elimination of a drug . in the methods of the present invention , the compounds herein described in detail can form the active ingredient , and are typically administered in admixture with suitable pharmaceutical diluents , excipients or carriers ( collectively referred to herein as &# 34 ; carrier &# 34 ; materials ) suitably selected with respect to the intended form of administration , that is , oral tablets , capsules , elixirs , syrups and the like , and consistent with conventional pharmaceutical practices . for instance , for oral administration in the form of a tablet or capsule , the active drug component can be combined with an oral , non - toxic pharmaceutically acceptable inert carrier such as ethanol , glycerol , water and the like . moreover , when desired or necessary , suitable binders , lubricants , disintegrating agents and coloring agents can also be incorporated into the mixture . suitable binders include , without limitation , starch , gelatin , natural sugars such as glucose or beta - lactose , corn sweeteners , natural and synthetic gums such as acacia , tragacanth or sodium alginate , carboxymethylcellulose , polyethylene glycol , waxes and the like . lubricants used in these dosage forms include , without limitation , sodium oleate , sodium stearate , magnesium stearate , sodium benzoate , sodium acetate , sodium chloride and the like . disintegrators include , without limitation , starch , methyl cellulose , agar , bentonite , xanthan gum and the like . the liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums , for example , tragacanth , acacia , methyl - cellulose and the like . other dispersing agents which may be employed include glycerin and the like . for parenteral administration , sterile suspensions and solutions are desired . isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired . the compounds of the present invention can also be administered in the form of liposome delivery systems , such as small unilamellar vesicles , large unilamellar vesicles and multilamellar vesicles . liposomes can be formed from a variety of phospholipids , such as cholesterol , stearylamine or phosphatidylcholines . compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled . the compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers . such polymers can include polyvinylpyrrolidone , pyran copolymer , polyhydroxypropylmethacrylamidephenol , polyhydroxy - ethylaspartamidephenol , or polyethyleneoxidepolylysine substituted with palmitoyl residues . furthermore , the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug , for example , polylactic acid , polyepsilon caprolactone , polyhydroxy butyric acid , polyorthoesters , polyacetals , polydihydro - pyrans , polycyanoacrylates and cross - linked or amphipathic block copolymers of hydrogels . compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever specific blockade of the human alpha 1a adrenergic receptor is required . the daily dosage of the products may be varied over a wide range from 0 . 01 to 1 , 000 mg per adult human per day . for oral administration , the compositions are preferably provided in the form of tablets containing 0 . 01 , 0 . 05 , 0 . 1 , 0 . 5 , 1 . 0 , 2 . 5 , 5 . 0 , 10 . 0 , 15 . 0 , 25 . 0 , 50 . 0 , 100 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated . a medicament typically contains from about 0 . 01 mg to about 500 mg of the active ingredient , preferably , from about 1 mg to about 100 mg of active ingredient . an effective amount of the drug is ordinarily supplied at a dosage level of from about 0 . 0002 mg / kg to about 250 mg / kg of body weight per day . preferably , the range is from about 0 . 001 to 100 mg / kg of body weight per day , and especially from about 0 . 001 mg / kg to 7 mg / kg of body weight per day . the compounds may be administered on a regimen of 1 to 4 times per day . compounds of this patent disclosure may be used alone at appropriate dosages defined by routine testing in order to obtain optimal antagonism of the human alpha 1a adrenergic receptor while minimizing any potential toxicity . in addition , co - administration or sequential administration of other agents which alleviate the effects of bph is desirable . thus , in one embodiment , this includes administration of compounds of this invention and a human testosterone 5 - α reductase inhibitor . included with this embodiment are inhibitors of 5 - alpha reductase isoenzyme 2 . many such compounds are now well known in the art and include such compounds as proscar ®, ( also known as finasteride , a 4 - aza - steroid ; see u . s . pat . nos . 4 , 377 , 584 and 4 , 760 , 071 , for example , hereby incorporated by reference ). in addition to proscar ®, which is principally active in prostatic tissue due to its selectivity for human 5 - a reductase isozyme 2 , combinations of compounds which are specifically active in inhibiting testosterone 5 - alpha reductase isozyme 1 and compounds which act as dual inhibitors of both isozymes 1 and 2 , are useful in combination with compounds of this invention . compounds that are active as 5a - reductase inhibitors have been described in wo93 / 23420 , ep 0572166 ; wo 93 / 23050 ; wo93 / 23038 , ; wo93 / 23048 ; wo93 / 2304 1 ; wo93 / 23040 ; wo93 / 23039 ; wo93 / 23376 ; wo93 / 23419 , ep 0572165 ; wo93 / 23051 , each of which is hereby incorporated by reference . the dosages of the alpha 1a adrenergic receptor and testosterone 5 - alpha reductase inhibitors are adjusted when combined to achieve desired effects . as those skilled in the art will appreciate , dosages of the 5 - alpha reductase inhibitor and the alpha 1a adrenergic receptor antagonist may be independently optimized and combined to achieve a synergistic result wherein the pathology is reduced more than it would be if either agent were used alone . in accordance with the method of the present invention , the individual components of the combination can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms . the instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term &# 34 ; administering &# 34 ; is to be interpreted accordingly . thus , in one preferred embodiment of the present invention , a method of treating bph is provided which comprises administering to a subject in need of treatment any of the compounds of the present invention in combination with finasteride effective to treat bph . the dosage of finasteride administered to the subject is about 0 . 01 mg per subject per day to about 50 mg per subject per day in combination with an alpha 1a antagonist . preferably , the dosage of finasteride in the combination is about 0 . 2 mg per subject per day to about 10 mg per subject per day , more preferably , about 1 to about 7 mg per subject to day , most preferably , about 5 mg per subject per day . for the treatment of benign prostatic hyperplasia , compounds of this invention exhibiting alpha ` ba adrenergic receptor blockade can be combined with a therapeutically effective amount of a 5α - reductase 2 inhibitor , such as finasteride , in addition to a 5α - reductase 1 inhibitor , such as 4 , 7β - dimethyl - 4 - aza - 5α - cholestan - 3 - one , in a single oral , systemic , or parenteral pharmaceutical dosage formulation . alternatively , a combined therapy can be employed wherein the alpha 1a adrenergic receptor antagonist and the 5α - reductase 1 or 2 inhibitor are administered in separate oral , systemic , or parenteral dosage formulations . see , e . g ., u . s . pat . no .&# 39 ; s 4 , 377 , 584 and 4 , 760 , 071 which describe dosages and 3 0 formulations for 5α - reductase inhibitors . abbreviations used in the instant specification , particularly the schemes and examples , are as follows : the compounds of the present invention can be prepared readily according to the following reaction schemes and examples , or modifications thereof , using readily available starting materials , reagents and conventional synthesis procedures . in these reactions , it is also possible to make use of variants which are themselves known to those of ordinary skill in this art , but are not mentioned in greater detail . unless otherwise indicated , all variables are as defined above . the preparation of 4 , 4 - disubstituted piperidines 4 was accomplished via spiro annulation of substituted acetonitrile derivatives 1 with n - boc bischloroethyl amine under basic conditions , typically nah in dmf at 80 ° c . in good yields , scheme 1 . the resulting 4 - cyano 4 - phenylpiperidines 3 were either : 1 ) n - boc deprotected with hcl - etoac or 2 ) the nitrile hydrolyzed to the corresponding carboxylic acid with concomitant n - boc deprotection with concentrated aqueous hcl and converted to esters and amides via simple coupling reactions to targeted derivatives 4 . in some instances the amino acids derived from treatment of 3 with concentrated aqueous hcl required n - boc protection prior to the coupling reactions to limit oligomerization . ## str6 ## the preparation of 3 , 4 - disubstituted piperidines 8 and 10 was accomplished in a simple two step fashion , scheme 2 . the vinyl triflate 6 , derived from n - boc 3 - carboxyethyl 4 - piperidinone was coupled under pd catalysis to aryl boronic acids and aryl stannanes in excellent yields . the resulting α , β - unsaturated esters 7 were reduced with hydrogen and pd - c providing the (±)- cis enantiomeric pair 8 . at this stage several pathways were pursued : ( 1 ) the (±)- cis racemate 8 was deprotected yielding 9 , ( 2 ) the (±)- cis enantiomeric pair 8 was converted to (±)- trans 10 via epimerization to the diequitorial isomer with the use of sodium ethoxide , then the resulting 10 (±)- trans was deprotected providing 11 , ( 3 ) the mixture (±)- cis enantiomers 8 was separated using normal phase chiral hplc providing 8a (-)- cis and 8b (+)- cis and 8a was then deprotected providing 9a . ## str7 ## the commercially available amino alcohol 12 was converted to the corresponding chloride 13 via treatment with thionyl chloride , scheme 3 . the chloride 13 was displaced by aniline in toluene at 180 ° c . providing anilinoethylbenzyl amine 14 . treatment of 14 with 2 - chloroacrylonitrile in dmf provided the desired cyano piperazine 15 . n - benzyl deprotection was accomplished using ace - cl in dichloroethane followed by treatment with methanol supplying the cyano piperazine 16 . piperazines 15 and 16 were separated easily utilizing chiral hplc technology and each enantiomer was evaluated individually , 15a and 15b , and 16a and 16b , respectively . ## str8 ## preferred compounds of the present invention are shown below in table 1 . the compounds of the present invention can be prepared by one of ordinary skill in the art following the schemes and examples set forth herein , substituting the appropriate readily available staring materials . table 1______________________________________1 # str9 ## r . sup . 1 r . sup . 2 r . sup . 3 a r2 / r3______________________________________4a h h h c na4b h co . sub . 2 ch . sub . 3 h c na4c h co . sub . 2 ch . sub . 2 ch . sub . 3 h c na4d h co . sub . 2 ( ch . sub . 2 ). sub . 3 ch . sub . 3 h c na4e h co . sub . 2 cyclohexyl h c na4f h cn h c na4g h conh . sub . 2 h c na4h h co . sub . 2 h h c na4i ch . sub . 3 cn h c na4j cl cn h c na4k cl co . sub . 2 ch . sub . 3 h c na4l cf . sub . 3 cn h c na4m och . sub . 3 cn h c na4n cn cn h c na4o conh . sub . 2 cn h c na9 h h co . sub . 2 ch . sub . 2 ch . sub . 3 c (±)- cis11 h h co . sub . 2 ch . sub . 2 ch . sub . 3 c (±)- trans9b h h co . sub . 2 ch . sub . 2 ch . sub . 3 c (+)- cis9a h h co . sub . 2 ch . sub . 2 ch . sub . 3 c (-)- cis16a h -- cn n isomer a16b h -- cn n isomer b______________________________________ in addition to the compounds disclosed above in table 1 , 4 - cyano4 -( 2 - pyridyl ) piperidine was also prepared . the following examples are provided to further define the invention without , however , limiting the invention to the particulars of these examples . a solution of n -( 2 , 2 &# 39 ;- bischloro ) diethyl amine ( 23 . 0 g , 0 . 130 mol ) and di - tert - butyl dicarbonate ( 28 . 8 g , 0 . 130 mol ) in ch 2 cl 2 ( 150 ml ) was treated with n , n - diisopropylethylamine ( 22 . 52 ml , 0 . 720 mol ) at room temperature ( 1 . 5 h ). the solvent was removed in vacuo and the residue was triturated with ether ( 300 ml ). the ether solution was collected and concentrated in vacuo affording n -( 2 , 2 &# 39 ;- bischloro )- diethyl - n -( 1 , 1 - dimethylethoxy ) carbonyl amine as a clear oil . 1 h nmr ( cdcl 3 , 400 mhz ) d 3 . 65 ( m , 8h ), 1 . 52 ( s , 9h ) fablrms ( 3 : 1 mixture of dithiothreitol and dithioerythritol in meoh ) m / e 242 g / mole ( m + + h , c 25 h 29 n 2 o 5 scl = 242 . 2 g / mole .) a solution of bis ( 2 - chloroethyl )- n -( 1 , 1 - dimethylethoxy ) carbonyl amine ( 1 . 438 g , 5 . 94 mmol ) and 2 - methylphenyl acetonitrile ( 600 mg , 3 . 96 mmol ) in a 4 : 1 mixture of thf / dmf ( 15 ml ) was treated with nah ( 357 . 9 mg , 8 . 7 mmol ) at 60 ° c . ( 3 d ). the solvent was removed in vacuo , the residue dissolved in etoac ( 200 ml ) and washed with saturated nahco3 ( 50 ml ), h20 ( 2 × 50 ml ), and saturated aqueous nacl ( 50 ml ), dried ( na 2 so 4 ) and concentrated in vacuo . pctlc ( sio 2 , 6mm , 100 % hexane ) afforded 4 - cyano - n -( 1 , 1 - dimethylethoxy ) carbonyl - 4 -( 2 - methylphenyl ) piperidine as a yellow / orange oil . 1 h nmr ( cdcl 3 , 400 mhz ) d 7 . 25 ( m , 4h ), 4 . 28 ( br s , 2h ), 3 . 28 ( br t , 2h ), 2 . 65 ( s , 3h ), 2 . 32 ( d , 2h , j = 13 . 0 hz ), 2 . 32 ( dt 2h , j = 4 . 1 , 13 . 0 hz ), 1 . 48 ( s , 9h ). hplc ( vydac ; c18 ; diameter = 4 . 6 mm ; length = 15 cm ; gradient = ch 3 cn 0 . 1 % tfa ! - h 2 o 0 . 1 % tfa !, 5 %- 95 %, 95 - 5 % over 20 min . 1 . 5 ml / min flow rate ; rt = 11 . 730 min ; focus = 215 nm ; 75 % pure . a solution of etoac saturated with hcl ( 200 ml ) was added to 4 - cyano - n -( 1 , 1 - dimethylethoxy ) carbonyl - 4 -( 2 - methylphenyl ) piperidine ( 31 mg , 0 . 097 mmol ). the resulting mixture was allowed to react for 1 hour at room temperature . the etoac was removed in vacuo affording 4 - cyano - 4 -( 2 - methylphenyl ) piperidine hydrochloride ( 4i ) as a white solid . 1 h nmr ( cd 3 od , 400 mhz ) d 7 . 37 ( m , 1i ), 7 . 32 ( m , 3h ), 3 . 64 ( dd , 2h , j = 2 . 2 , 11 . 4 hz ), 3 . 46 ( t , 2h , j = 13 . 5 hz ), 2 . 64 ( m , 2h ), 2 . 65 ( s , 3h ), 2 . 28 ( t d , 2h , j = 3 . 7 hz , 13 . 5 hz ). fablrms ( 3 : 1 mixture of dithiothreitol and dithioerythritol in meoh ) m / e 201 g / mole ( m + + h , c13h16n2 = 201 . 3 g / mole .) hplc ( vydac ; c18 ; diameter = 4 . 6 mm ; length = 15 cm ; gradient = ch 3 cn 0 . 1 % tfa ! - h 2 o 0 . 1 % tfa !, 5 %- 95 %, 95 - 5 % over 20 min . 1 . 5 ml / min flow rate ; rt 5 . 82 min ; focus = 215 nm ; 100 % pure . anal . calcd for c 13 h 16 n 2 . hcl and 0 . 30 h 2 o and 0 . 25 ch 2 cl 2 : c = 60 . 42 , h = 6 . 93 , n = 10 . 64 . found : c = 60 . 37 , h = 6 . 83 , n = 11 . 09 . a solution of bis ( 2 - chloroethyl )- n -( 1 , 1 - dimethylethoxy ) carbonyl amine ( 9 . 298 g , 38 . 4 mmol ) and 2 - chlorophenylacetonitrile ( 5 . 0 g , 32 . 0 mmol ) in a 4 : 1 mixture of thf / dmf ( 15 ml ) was treated with nah ( 2 . 82 g , 70 . 4 mmol ) at 60 oc ( 7 d ). the solvent was removed in vacuo , the residue dissolved in etoac ( 200 ml ) and washed with saturated nahco 3 ( 50 ml ), h 2 o ( 2 × 50ml ), and saturated aqueous nacl ( 50 ml ), dried na 2 so 4 ) and concentrated in vacuo . trituration of the residue with 100 % meoh afforded 4 -( 2 - chlorophenyl ) 4 - cyano - n -( 1 , 1 - dimethylethoxy ) carbonyl piperidine as a white solid . 1 h nmr ( cd 3 od , 400 mhz ) d 7 . 53 ( m , 2h ), d 7 . 41 ( m , 2h ), 4 . 28 ( br dd , 2h , j = 13 . 4 hz ), 3 . 26 ( m , 2h ), 2 . 52 ( dd , 2h , j = 2 . 2 , 11 . 2 hz ), 2 . 03 ( dt , 2h , j = 4 . 0 , 9 . 2 hz ), 2 . 03 ( s , 9h ). fablrms ( 3 : 1 mixture of dithiothreitol and dithioerythritol in meoh ) m / e 321 g / mole ( m + + h , c 17 h 21 n 2 o 2 cl = 320 . 8 g / mole .) hplc ( vydac ; c18 ; diameter = 4 . 6 mm ; length = 15 cm ; gradient = ch 3 cn 0 . 1 % tfa ! - h 2 o 0 . 1 % tfa !, 5 %- 95 %, 95 - 5 % over 20 min . 1 . 5 ml / min flow rate ; rt = 11 . 70 min ; focus = 215 mm ; 97 . 4 % pure . a solution of etoac saturated with hcl ( 200 ml ) was added to 4 -( 2 - chlorophenyl )- 4 - cyano - n -( 1 , 1 - dimethylethoxycarbonyl ) piperidine , ( 880 mg , 2 . 74 mmol ). the resulting mixture was allowed to react for 1 hour at room temperature . the etoac was removed in vacuo affording 4 -( 2 - chlorophenyl )- 4 - cyanopiperidine hydrochloride ( 4j ) as a white solid . 1 h nmr ( cd 3 od , 400 mhz ) d 7 . 53 ( dd , 1h , j = 2 . 0 , 4 . 3 hz ), 7 . 5 ( dd , 1h , j = 2 . 0 , 5 . 3 hz ), 7 . 40 ( ddd , 2h , j = 2 . 0 , 6 . 0 , 7 . 9 hz ), 3 . 14 ( ddd , 4h , j = 2 . 2 , 10 . 8 , 12 . 4 hz ), 2 . 51 ( dd , 2h , j = 2 . 2 , 13 . 5 hz ), 2 . 00 ( dt , 2h , j = 3 . 4 , 13 . 5 hz ). fablrms ( 3 : 1 mixture of dithiothreitol and dithioerythritol in meoh ) m / e 221 g / mole ( m + + h , c13h16n2 = 220 . 7 g / mole .) hplc ( vydac ; c18 ; diameter = 4 . 6 mm ; length = 15 cm ; gradient = ch 3 cn 0 . 1 % tfa ! - h 2 o 0 . 1 % tfa !, 5 %- 95 %, 95 - 5 % over 20 min . 1 . 5 ml / min flow rate ; rt = 5 . 744 min ; focus = 215 nm ; 99 . 04 % pure . anal . calcd for c 12 h 13 n 2 cl . hcl and 0 . 60 h 2 o : c = 62 . 26 , h = 6 . 18 , n = 12 . 10 . found : c = 62 . 29 , h = 5 . 69 , n = 11 . 71 . a solution of n - benzyl - 2 - aminoethanol ( 12 , 79 . 05 g , 0 . 523 mole ) in chloroform ( 400 nil ) was treated with thionyl chloride ( 80 ml , 1 . 09 mole ) at room temperature . the resulting mixture was heated to reflux ( 6 h ). the solvent was removed in vacuo , the residue dissloved in hot ethanol ( 1 . 3 l ) and cooled overnight . the solids were collected via suction filtration and dried in vacuo at 65 ° c . ( 24 h ) to afford the title compound 13 as white plates . a solution of 13 ( 8 . 618 g , 42 . 0 mmol ) and aniline ( 11 . 75 g , 126 mmol ) in toluene ( 40 nil ) was heated to 130 ° c . ( 1 . 5 h ). the mixture was triturated with dichloromethane ( 200 ml ) and filtered . recrystallization from ethanol ( 220 ml ) afforded the title compound 14 as white crystals . 1 h nmr ( dmso , 400 mhz ) δ 7 . 59 ( dd , 2h , j = 1 . 93 , 7 . 64 hz ), 7 . 42 ( m , 3h ), 7 . 10 ( t , 2h , 7 . 98 hz ), 6 . 59 ( m , 3h ), 5 . 95 ( s , 1h ), 4 . 17 ( s , 2h ), 3 . 41 ( t , 2h , j = 6 . 38 hz ), 3 . 04 ( t , 2h , j = 6 . 55 hz ). fablrms m / e 241 g / mole ( m + + h , c 16 h 20 n 2 = 241 g / mole .) hplc ( vydac ; c18 ; diameter = 4 . 6 mm ; length = 150 mm ; gradient = h 2 o 0 . 1 % h 3 po 4 ! - ch 3 cn , 95 %- 5 %, 5 %- 95 %, over 16 minutes , 2 ml / min flow rate ) rt = 7 . 371 min ; focus = 215 nm ; 99 . 3 % pure . a solution of 14 ( 5 . 07 g , 17 . 0 mmol ) and diisopropylethylamine ( 4 . 97 g , 38 . 4 mmol ) in dmf ( 40 nl ) was treated with a solution of 2 - cyanoacrylonitrile ( 2 . 30 g , 26 . 3 mmol ) in dmp ( 40 ml ) at room temperature ( 14 d ). the solvent was removed in vacuo and the residue dissolved in dichloromethane and washed with water , brine , and dried ( na 2 so 4 ). concentrated in vacuo , the residue was recrystallized from ethanol to afford 15 as white crystals . 1 h nmr ( cdcl 3 , 400 mhz ) δ 7 . 34 ( m , 7h ), 7 . 00 ( t , 3h , j = 8 . 31 hz ), 4 . 53 ( s , 1h ), 3 . 72 ( d , 1h , j = 13 . 26 hz ), 3 . 59 ( d , 1h , 13 . 43 hz ), 3 . 40 ( d , 1h , j = 11 . 91 hz ), 3 . 28 ( td , 1h , j = 3 . 13 , 11 . 59 hz ), 3 . 13 ( dt , 1h , j2 . 26 , 11 . 42 hz ), 3 . 01 ( dq , 1h , j = 2 . 43 , 11 . 08 hz ), 2 . 53 ( dd , 1h , j = 3 . 19 , 11 . 41 hz ), 2 . 39 ( td , 1h , j = 3 . 36 , 11 . 25 hz ). fablrms m / e 278 g / mole ( m ++ h , c 18 h 20 n 3 = 278 g / mole .) hplc ( vydac ; c18 ; diameter = 4 . 6 mm ; length = 150 mm ; gradient = h 2 o 0 . 1 % h 3 po 4 !-- ch 3 cn , 95 %- 5 %, 5 %- 95 %, over 16 minutes , 2 ml / min flow rate ) rt = 7 . 936 min ; focus 215 nm ; 100 % pure . anal . calcd for c 18 h 19 n 3 · 0 . 15 h 2 o : c = 77 . 19 , h = 6 . 95 , n = 15 . 00 . found : c = 77 . 14 , h = 6 . 90 , n = 14 . 88 . a solution of 15 ( 3 . 40 g , 12 . 25 mmol ) in 1 , 2 - dichloroethane ( 60 ml ) was treated with alpha - chloroethyl - chloroformate ( 3 . 78 g , 26 . 44 mmol ) at 0 ° c . the reaction mixture was heated to 100 ° c . ( 8 h ). the solvent was removed in vacuo and the residue dissolved in methanol ( 80 ml ) at room temperature ( overnight ). the solvent was removed in vacuo and the residue was recrystallized from ethanol ( 160 ml ) to afford crystalline 16 . 1 h nmr ( dmso , 400 mhz ) δ 9 . 74 ( s , 1h ), 7 . 36 ( m , 2h ), 7 . 12 ( d , 2h , j = 7 . 89 hz ), 7 . 03 ( t , 1h , j = 7 . 31 hz ), 5 . 48 ( d , 1h , j = 4 . 03 hz ), 3 . 75 ( d , 2h , j = 13 . 09 hz ), 3 . 43 ( dd , 1h , j = 4 . 53 , 13 . 43 hz ), 3 . 38 ( d , 2h , j = 10 . 74 hz ), 3 . 07 ( m , 2h ). fablrms m / e 188 g / mole ( m + + h , cl 1 h 14 n 3 = 188 g / mole .) hplc ( vydac ; c18 ; diameter = 4 . 6 mm ; length = 150 mm ; gradient = h 2 o 0 . 1 % h 3 po 4 ! - ch 3 cn , 95 %- 5 %, 5 %- 95 %, over 16 minutes , 2 ml / min flow rate ) rt = 3 . 563 min ; focus = 215 nm ; 100 % pure . anal . calcd for c 11 h 13 n 3 · 1 . 00 hcl : c = 59 . 06 , h = 6 . 31 , n = 18 . 79 . found : c = 59 . 27 , h = 6 . 37 , n = 18 . 42 . the enantiomeric mixture was separated utilizing normal phase chiral hplc ( chiralcel od , 2 . 0 cm ≅ 25 cm , 65 hexanes / 35 2 - propanol / 0 . 2 diethyl amine , 2 . 5 ml / min ). each enantiomer possessed identical spectroscopic properties but opposite signs of optical rotation . chiral purity was assessed utilizing similar hplc conditions ( chiralcel od , 4 . 6 mm × 25 cm , 65 hexanes / 35 2 - propanol / 0 . 2 diethyl amine , 0 . 7 ml / min ). the enantiomeric mixture was separated utilizing normal phase chiral hplc ( chiralcel od , 2 . 0 cm × 25 cm , 65 hexanes / 35 2 - propanol / 0 . 2 diethyl amine , 2 . 5 ml / min ). each enantiomer possessed identical spectroscopic properties but opposite signs of optical rotation . chiral purity was assessed utilizing similar hplc conditions ( chiralcel od , 4 . 6 mm × 25 cm , 65 hexanes / 35 2 - propanol / 0 . 2 diethyl amine , 0 . 7 ml / min ). as a specific embodiment of an oral composition , 100 mg of the compound of example 3 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size o hard gel capsule . membranes prepared from the stably transfected human alpha 1a cell line ( atcc crl 11140 ) were used to identify compounds that bind to the human alpha 1a adrenergic receptor . these competition binding reactions ( total volume = 200 μl ) contained 50 mm tris - hcl ph . 7 . 4 , 5 mm edta , 150 mm nacl , 100 pm 125 i !- heat , membranes prepared from the alpha 1a cell line and increasing amounts of unlabeled ligand . reactions were incubated at room temperature for one hour with shaking . reactions were filtered onto whatman gf / c glass fiber filters with a inotec 96 well cell harvester . filters were washed three times with ice cold buffer and bound radioactivity was determined ( ki ). representative compounds of the present invention were found to have ki values ≦ 500 nm . membranes prepared from stably transfected human alpha 1d and alpha 1b cell lines ( atcc crl 11138 and crl 11139 , respectively ) were used to identify compounds that selectively bind to the human alpha 1a adrenergic receptor . these competition binding reactions ( total volume = 200 μl ) contained 50 mm tris - hcl ph . 7 . 4 , 5 mm edta , 150 mm nacl , 100 pm 125 i !- heat , membranes prepared from cell lines transfected with the respective alpha 1 subtype expression plasmid and increasing amounts of unlabeled ligand . reactions were incubated at room temperature for one hour with shaking . reactions were filtered onto whatman gf / c glass fiber filters with a inotec 96 well cell harvester . filters were washed three times with ice cold buffer and bound radioactivity was determined ( ki ). 1 . assay title : dopamine d 2 , d 3 , d 4 in vitro screen the objective of this assay is to eliminate agents which specifically affect binding of 3h ! spiperone to cells expressing human dopamine receptors d 2 , d 3 or d 4 . modified from vantol et al ( 1991 ); nature ( vol 350 ) pg 610 - 613 . frozen pellets containing specific dopamine receptor subtypes stably expressed in clonal cell lines are lysed in 2 ml lysing buffer ( 10 mm tris - hcl / 5mm mg , ph 7 . 4 ). pellets obtained after centrifuging these membranes ( 15 &# 39 ; at 24 , 450 rpm ) are resuspended in 50 mm tris - hcl ph 7 . 4 containing edta , mgcl 2 !, kcl , nacl , cacl 2 ! and ascorbate to give a 1 mg / nil suspension . the assay is initiated by adding 50 - 75 μg membranes in a total volume of 500 μl containing 0 . 2 nm 3h !- spiperone . non - specific binding is defined using 10 gm apomorphine . the assay is terminated after a 2 hour incubation at room temperature by rapid filtration over gf / b filters presoaked in 0 . 3 % pei , using 5omm tris - hcl ph 7 . 4 . the objective of this assay is to eliminate agents which specifically affect binding to cloned human 5ht1a receptor mammalian cells expressing cloned human 5ht1a receptors are lysed in ice - cold 5 mm tris - hcl , 2 mm edta ( ph 7 . 4 ) and homogenized with a polytron homogenizer . the homogenate is centrifuged at 1000 × g for 30 &# 39 ;, and then the supernatant is centrifuged again at 38 , 000 × g for 30 &# 39 ;. the binding assay contains 0 . 25 nm 3h ! 8 - oh - dpat ( 8 - hydroxy - 2 - dipropylamino - 1 , 2 , 3 , 4 - tetrahydronaphthalene ) in 50 mm tris - hcl , 4 mm cacl2 and 1 mg / ml ascorbate . non - specific binding is defined using 10 μm propranolol . the assay is terminated after a 1 hour incubation at room temperature by rapid filtration over gf / cfilters . in order to confirm the specificity of compounds for the human alpha 1a adrenergic receptor and to define the biological activity of the compounds , the following functional tests may be performed : taconic farms sprague - dawley male rats , weighing 250 - 400 grams are sacrificed by cervical dislocation under anesthesia ( methohexital ; 50 mg / kg , i . p .). an incision is made into the lower abdomen to remove the ventral lobes of the prostate . each prostate removed from a mongrel dog is cut into 6 - 8 pieces longitudinally along the urethra opening and stored in ice - cold oxygenated krebs solution overnight before use if necessary . dog urethra proximal to prostate is cut into approximately 5 mm rings , the rings are then cut open for contractile measurement of circular muscles . human prostate chips from transurethral surgery of benign prostate hyperplasia are also stored overnight in ice - cold krebs solution if needed . the tissue is placed in a petri dish containing oxygenated krebs solution nacl , 118 mm ; kcl , 4 . 7 mm ; cacl 2 , 2 . 5 mm ; kh 2 po 4 , 1 . 2 mm ; mgso 4 , 1 . 2 mm ; nahco 3 , 2 . 0 mm ; dextrose , 11 mm ! warmed to 37 ° c . excess lipid material and connective tissue are carefully removed . tissue segments are attached to glass tissue holders with 4 - 0 surgical silk and placed in a 5 ml jacketed tissue bath containing krebs buffer at 37 ° c ., bubbled with 5 % co 2 / 95 % o 2 . the tissues are connected to a statham - gould force transducer ; 1 gram ( rat , human ) or 1 . 5 gram ( dog ) of tension is applied and the tissues are allowed to equilibrate for one hour . contractions are recorded on a hewlett - packard 7700 series strip chart recorder . after a single priming dose of 3 μm ( for rat ), 10 μm ( for dog ) and 20 μm ( for human ) of phenylephrine , a cumulative concentration response curve to an agonist is generated ; the tissues are washed every 10 minutes for one hour . vehicle or antagonist is added to the bath and allowed to incubate for one hour , then another cumulative concentration response curve to the agonist is generated . ec 50 values are calculated for each group using graphpad inplot software . pa2 (˜ log kb ) values were obtained from schild plot when three or more concentrations were tested . when less than three concentrations of antagonist are tested , k b values are calculated according to the following formula ## equ1 ## where x is the ratio of ec 50 of agonist in the presence and absence of antagonist and b ! is the antagonist concentration . purpose : benign prostatic hyperplasia causes a decreased urine flow rate that may be produced by both passive physical obstruction of the prostatic urethra from increased prostate mass as well as active obstruction due to prostatic contraction . alpha adrenergic receptor antagonists such as prazosin and terazosin prevent active prostatic contraction , thus improve urine flow rate and provide symptomatic relief in man . however , these are non - selective alpha 1 receptor antagonists which also have pronounced vascular effects . because we have identified the alpha 1 a receptor subtype as the predominent subtype in the human prostate , it is now possible to specifically target this receptor to inhibit prostatic contraction without concomitant changes in the vasculature . the following model is used to measure adrenergically mediated changes in intra - urethral pressure and arterial pressure in anesthetized dogs in order to evaluate the efficacy and potency of selective alpha adrenergic receptor antagonists . the goals are to : 1 ) identify the alpha 1 receptor subtypes responsible for prostatic / urethral contraction and vascular responses , and 2 ) use this model to evaluate novel selective alpha adrenergic antagonists . novel and standard alpha adrenergic antagonists may be evaluated in this manner . methods : male mongrel dogs ( 7 - 12 kg ) are used in this study . the dogs are anesthetized with pentobarbital sodium ( 35 mg / kg , i . v . plus 4 mg / kg / hr iv infusion ). an endotracheal tube is inserted and the animal ventilated with room air using a harvard instruments positive displacement large animal ventilator . catheters ( pe 240 or 260 ) are placed in the aorta via the femoral artery and vena cava via the femoral veins ( 2 catheters , one in each vein ) for the measurement of arterial pressure and the administration of drugs , respectively . a supra - pubic incision ˜ 1 / 2 inch lateral to the penis is made to expose the urethers , bladder and urethra . the urethers are ligated and cannulated so that urine flows freely into beakers . the dome of the bladder is retracted to facilitate dissection of the proximal and distal urethra . umbilical tape is passed beneath the urethra at the bladder neck and another piece of umbilical tape is placed under the distal urethra approximately 1 - 2 cm distal to the prostate . the bladder is incised and a millar micro - tip pressure transducer is advanced into the urethra . the bladder incision is sutured with 2 - 0 or 3 - 0 silk ( purse - string suture ) to hold the transducer . the tip of the transducer is placed in the prostatic urethra and the position of the millar catheter is verified by gently squeezing the prostate and noting the large change in urethral pressure . phenylephrine , an alpha 1 adrenergic agonist , is administered ( 0 . 1 - 100 ug / kg , iv ; 0 . 05 ml / kg volume ) in order to construct dose response curves for changes in intra - urethral and arterial pressure . following administration of increasing doses of an alpha adrenergic antagonist ( or vehicle ), the effects of phenylephrine on arterial pressure and intra - urethral pressure are re - evaluated . four or five phenylephrine dose - response curves are generated in each animal ( one control , three or four doses of antagonist or vehicle ). the relative antagonist potency on phenylephrine induced changes in arterial and intra - urethral pressure are determined by schild analysis . the family of averaged curves are fit simultaneously ( using allfit software package ) with a four paramenter logistic equation constraining the slope , minimum response , and maximum response to be constant among curves . the dose ratios for the antagonist doses ( rightward shift in the dose - response curves from control ) are calculated as the ratio of the ed 50 &# 39 ; s for the respective curves . these dose - ratios are then used to construct a schild plot and the kb ( expressed as ug / kg , iv ) determined . the kb ( dose of antagonist causing a 2 - fold rightward shift of the phenylephrine dose - response curve ) is used to compare the relative potency of the antagonists on inhibiting phenylephrine responses for intra - urethral and arterial pressure . the relative selectivity is calculated as the ratio of arterial pressure and intra - urethral pressure kb &# 39 ; s . effects of the alpha 1 antagonists on baseline arterial pressure are also monitored . comparison of the relative antagonist potency on changes in arterial pressure and intra - urethral pressure provide insight as to whether the alpha receptor subtype responsible for increasing intra - urethral pressure is also present in the systemic vasculature . according to this method , one is able to confirm the selectivity of alpha 1a adrenergic receptor antagonists that prevent the increase in intra - urethral pressure to phenylephrine without any activity at the vasculature . 3 h - naloxone binds with high affinity to opiate receptors in brain tissue ( creese and snyder , j . pharm expt . ther ., 194 : 205 - 219 , 1975 ). the potency of a compound to inhibit the specific binding of this radioligand gives a measure of the affinity for these receptors . 3 h - naloxone binding in rat brain membranes was performed as described by creese and snyder ( j . pharm . expt . ther ., 194 , 205 - 219 , 1975 ) using tris buffer alone or in the presence of 150 mm nacl . naloxone binding for representative examples of the present invention are ≧ 6 μm . while the foregoing specification teaches the principles of the present invention , with examples provided for the purpose of illustration , it will be understood that the practice of the invention encompasses all of the usual variations , adaptations and / or modifications as come within the scope of the following claims and their equivalents .