the continuing illicit 
 use of psychoactive substances , with the 
 resulting health and social consequences , emphasizes the need for 
 improved pharmacotherapies for drug abuse .
treatments for opiate abuse , 
 such as methadone and buprenorphine ( 1n ) , are available 
 and have proven successful against a range of addict populations
. 
 however , there are no such approved pharmacotherapies for cocaine 
 abuse , though a wide range of possible treatment agents have been 
 evaluated in the laboratory and in clinical trials .
there has been interest in the use of kappa opioid 
 receptor ( kor ) 
 agonists as potential pharmacotherapies for cocaine and other psychostimulant 
 abuse , particularly as repeated administration of kor agonists has been 
 shown to prevent or reduce many of cocaine s behavioral effects . primarily due to the dysphoric effects produced by 
 kor - agonists ,
the development of a kor - agonist pharmacotherapy for 
 human use is not straightforward .
for example , while enadoline ( ci-977 ) , 
 a high efficacy , selective kor - agonist , appeared to be better tolerated 
 in subjects with a history of drug use compared to naive individuals , 
 it still caused some dysphoria .
overall , 
 the evidence suggests that higher efficacy kor - agonists with some 
 additional mu opioid receptor ( mor)-agonist activity , such as ethylketazocine 
 ( ekc ) , are more effective in reducing cocaine self - administration , 
 and display fewer side effects , than their more kor - selective counterparts 
 such as enadoline and spiradoline .
presumably , 
 the presence of some mor - agonist effects helps attenuate any dysphoria 
 induced by the kor - agonism . in the treatment of opiate abuse , 
 a long - duration of action is 
 of benefit for successful treatment agents .
the main pharmacotherapies 
 methadone and buprenorphine ( 1n ) , but also laam , are 
 long acting , and their success is at least partly as a result of this 
 property . together with its reduced efficacy , 
 the slow onset of effects displayed by buprenorphine ( 1n ) appears to reduce its abuse potential .
ekc and the other kor - agonists 
 effective in reducing cocaine self - administration all have short duration 
 of action .
a strategy for the treatment 
 of cocaine abuse could therefore be the utilization of mixed kor - agonists / mor - partial 
 agonists having extended duration of action . of interest in this
regard 
 are the orvinols , a series of opioids displaying a range of pharmacological 
 profiles including the long - acting mor partial agonist 1n .
the orvinols have not previously been 
 thoroughly evaluated as kor - agonists , but it has become clear that 
 a number of them do display substantial kor - efficacy in vivo and that their lack of absolute kor - selectivity , in particular over 
 mor , makes them of particular interest to this project .
an early example 
 was the isopentyl orvinol m320 ( 5 : table 1 ) , 
 which was the subject of a detailed pharmacological study by boura 
 and fitzgerald .
compound 5 shows a kor / mor profile similar to that of ekc , but it is more potent 
 and very much longer acting . in this article
, we describe our initial 
 work toward analogues of 5 and 1n as potential 
 therapies for cocaine abuse .
there is a particular focus on orvinols 
 having a branched chain attached to c20 as these regions ( above and 
 away from c6/c7 and below c8 ) are associated with efficacy at kor .
only one significant change has been made to the synthetic route 
 and relates to how and when the n - methyl group is replaced with cyclopropylmethyl 
 in series 1 .
we have found that this process is most 
 reliably performed ( simpler and higher yielding ) with diisopropyl 
 azodicarboxylate ( diad ) on methyl ketone 6 ( scheme 1 ) .
series 24 were all synthesized from aldehyde 10 , itself 
 prepared from n - cyclopropylnorthebaine , the initial step being the addition of the appropriate 
 grignard reagent , which gave a mixture of diastereomeric secondary 
 alcohols , with the major isomer ( 11a ) as shown ( scheme 2 ) .
this major product in each case was isolated 
 in sufficient quantity to allow 3-o - demethylation to series 4 .
swern oxidation of 11a alone or the mixture 
 of diastereomeric alcohols gave ketones 12 that on treatment 
 with methylmagnesium bromide and subsequent 3-o - demethylation gave 
 the diastereomeric 3-alcohol series ( 2 ) .
reduction 
 of 12 gave the 2 alcohols 11b ( major 
 product ) and 11a ( minor product ) , with 3-o - demethylation 
 of 11b giving access to series 3 .
four series of orvinols 
 were studied . these were tertiary alcohols 
 having the same relative stereochemistry as buprenorphine ( 1a1n , scheme 1 ) , a more 
 limited series of diastereomeric tertiary alcohols ( 2a2i ) , secondary alcohols with the same relative 
 stereochemistry as buprenorphine ( 3a3i ) , and finally a series of diastereomeric secondary alcohols ( 4a4k ) ( scheme 2 ) .
binding affinities of the new compounds for mor and kor 
 were determined 
 by displacement of [ h]-diprenorphine binding from c6-rat 
 glioma cells expressing recombinant rat mor and cho cells expressing 
 recombinant human kor .
delta opioid receptor ( dor ) activity of the 
 new ligands was only determined for the ligands progressed to in vivo 
 studies as in no case has dor activity proved significant in the pharmacological 
 profile of orvinol based ligands .
as expected , all of the ligands 
 bound with high to very high affinity to both kor and mor with little 
 or no selectivity for one receptor over the other ( table 1 ) . if any selectivity was observed , it was for the 
 kor ( e.g. , 4b and 4d had 11-fold higher 
 affinity for kor than for mor ) .
affinities for kor were in the subnanomolar 
 range ( 0.015 to 0.22 nm ) for all of the ligands , with affinities for 
 the mor in the range 0.0291.0 nm .
binding affinities for five 
 of the ligands ( 1l , 1 m , 2 g , 2h , and 2i ) , all synthesized at an earlier time , 
 were evaluated in guinea pig brain membranes using established methods .
compound 1a was evaluated in both 
 binding assays , providing a reference to enable comparison with the 
 rest of the series .
affinities were lower in the guinea pig brain 
 membrane assay but confirmed the lack of selectivity , with equal affinity 
 for kor and mor .
affinities for 1b and 1c at dor were determined by displacement of [ h]-diprenorphine 
 binding from c6-rat glioma cells expressing recombinant dor .
they 
 bound with high affinity , with ki values 
 of 0.34 nm and 0.42 nm , respectively .
ki ( nm ) 
 versus [ h]diprenorphine ; values are an average  
 sem from three separate experiments .
percent maximal stimulation ( % 
 stim ) with respect to the standard agonists damgo ( mor ) and u69,593 
 ( kor ) ; values are an average  sem from three separate experiments ; 
 n.d . , not determined . binding 
 to hartley guinea pig membranes , ki ( nm ) 
 versus [ h]damgo ( mor ) and 
 [ h]u69,593 ( kor ) . 3b ke ( versus damgo ) 
 0.50  0.08
affinities 
 for 1b and 1c at dor were determined by 
 displacement of [ h]-diprenorphine binding from c6-rat 
 glioma cells expressing recombinant 
 dor ; ki values were 0.34  0.07 nm 
 and 0.42  0.18 nm , respectively .
efficacy at dor was 1b , 2.3  1.3% ; ec50 was not determined ; and 1c , 7.9  1.7% ; ec50 values were not determined .
the primary in vitro assay used to determine opioid 
 receptor functional activity was the [ s]gtps assay , 
 which , like the binding assays , was performed on recombinant opioid 
 receptors transfected into c6-rat glioma cells ( for mor ) and cho cells 
 ( for kor ) .
agonist efficacy at these 
 opioid receptors was determined in comparison to the standard selective 
 agonists damgo ( mor ) , and u69593 ( kor ) ( table 1 ) . in this assay , buprenorphine ( 1n )
displayed no efficacy 
 at kor , while m320 ( 5 ) was a very potent , full agonist 
 ( 91% stimulation ) .
the new compounds displayed a range of efficacies 
 at kor , from low efficacy partial agonists ( e.g. , 1a , 1d , 1j , and 3a had efficacies from 
 3049% ) to full agonists of equivalent efficacy to the standard 
 u69593 ( e.g. , most of series 4 and 2c , 2d , and 3i among others ) .
the majority 
 of ligands displayed lower efficacy at mor than at 
 kor ; the most extreme examples being 3b and 3i which are potent , full agonists at kor , with no efficacy at mor . 
 they proved to be potent mor antagonists shifting the concentration 
 effect curve for the standard agonist damgo in a parallel fashion 
 giving ke(mor ) of 0.50 nm and 0.35 nm , respectively .
substantial selectivity in efficacy for kor was seen in 
 a number of other ligands including 1b , 2b , 2c , 2d , 2f , 3 g , 4b , and 4d . within series 1 , 2 , and 3 ,
highest mor efficacy was typically 
 found with the cyclohexylmethyl and closely related benzyl side chains . 

compound 4h , having a cyclohexylmethyl side chain , also 
 had high efficacy , although in this series , 4j ( having 
 a benzyl group ) was only a partial agonist with moderate efficacy . 

the two ligands , 1b and 1c , evaluated at 
 dor were both of very low efficacy ( 2% and 8% stimulation , respectively ) .
five ligands ( 1l , 1 m , 2 g , 2h , and 2i ) were evaluated in the guinea 
 pig ileum ( gpi ) and mouse vas deferens ( mvd ) isolated tissue assays , 
 instead of [ s]gtps assays ( table 2 ) , using standard procedures .
compounds 1a and 1n were also tested in 
 these isolated tissue assays to allow meaningful comparison between 
 results from the different assays .
the gpi has both mor and kor populations 
 and is sensitive to kor agonist effects , while the mvd has all three 
 types of opioid receptors and is particularly sensitive to dor agonists 
 and least sensitive to kor agonists .
the n - propyl 
 analogue ( 1l ) and the diastereomeric n - pentyl analogue ( 2h ) were partial agonists in the gpi , 
 whereas the other ligands evaluated in this assay were all of higher 
 efficacy .
thus , 1l had lower efficacy than its i - propyl isomer 1a and also lower than the 
 bulky t - butyl containing 1n and also 1 m , having the longer n - pentyl chain .
compound 2 g , the diastereomer of 1l , was also of higher 
 efficacy as was the t - butyl containing 2i .
the effects of these ligands in the gpi could not readily be reversed 
 by the standard antagonists ctap and norbni .
each of the compounds 
 was found to be an antagonist in the mvd with 1a , 1l , and 1 m displaying some selectivity for mor . 

antagonist ke s at kor were not determined for 2 g and 2i as they had demonstrated efficacy in the gpi .
ke ( nm ) of the 
 selective antagonists 
 norbni ( kor ) and ctap ( mor ) versus test compound . n.r . :
antagonist 
 ke ( nm ) of the test compound 
 versus the standard agonists damgo ( mor ) , u69,593 ( kor ) , and dpdpe 
 ( dor ) .
comparative molecular field 
 analysis ( comfa ) is a technique used 
 to generate a description of a 3d structure  activity relationship 
 in a quantitative manner , i.e. , it is a 3d variant of a quantitative 
 structure  activity relationship ( qsar ) .
the output of a comfa 
 is a 3d model showing structural features of the input data that are 
 likely to affect , beneficially or adversely , the activity of the compounds . 
 a comfa was used to help identify the regions near c20 that are beneficial 
 or detrimental to kor efficacy and to help confirm the conformation 
 adopted by the different isomeric series on binding to the kor .
all 
 the compounds evaluated in the [ s]gtps assay , 
 including 1n and 5 , were used to develop 
 the model . with all compounds overlaid in their lowest energy ,
c6-ome 
 to c20-oh hydrogen bonded conformation ( as depicted for 1n in figure 1 ) and using the % stimulation 
 at kor data , an r of 0.911 and a cross - validated r of 0.447 were obtained .
as can be seen in 
 figure 1 , the model predicts that for high 
 kor efficacy there are two areas close to c20 that could beneficially 
 be occupied by lipophilic groups , the first is away from c7 and the 
 second is the region below c8 .
the model also suggests that lipophilic 
 groups closer to c20 are not well tolerated , leading to lower kor 
 efficacy .
evaluation of alternative conformations about the c7c20 
 bond ( e.g. , so that the bulky r group of series 1 and 3 occupies the region below c8 ) led to substantial reductions 
 in r and in particular the cross - validated r. two views of the areas , predicted by comfa analysis , 
 where interaction 
 with a lipophilic group would be beneficial for kor activation ( shown 
 in green ) and where interaction with a lipophilic group would be detrimental 
 to efficacy ( shown in yellow ) .
the docking of 1n to the recently published 
 crystal 
 structures of the mor and kor opioid receptors was examined .
the crystal 
 structure of the kor was determined in 
 the presence of the selective kor antagonist jdtic and presumably 
 represents the antagonist conformation of the receptor .
jdtic is enclosed 
 in a largely hydrophobic pocket with only one direct hydrogen bond 
 to the protein .
there is a network of water - mediated hydrogen bonds 
 between the ligand and the protein .
the docked 1n structure 
 overlays the 7-hydroxy - tetrahydroisoquinoline with the buprenorphine 
 phenolic hydroxy group making the same interactions as the equivalent 
 group in jdtic ( figure 2 ) .
there is a hydrogen 
 bond between the protonated nitrogen and the side chain of asp138 . 

the isopropyl group of jdtic fits into and fills a tight pocket formed 
 by val108 , asn141 , trp287 , and tyr320 : this interaction is replicated 
 by the cyclopropyl moiety of 1n .
the t - butyl group makes no specific interactions with the protein but 
 projects into the large pocket that the phenylpiperidine motif of 
 jdtic occupies .
kor with the protein in green , the crystal structure ligand 
 ( jdtic ) 
 in cyan , and the docked buprenorphine ( 1n ) in pink . the 
 hydrogen bond between the docked ligand and asp138 is shown as the 
 black dashed line .
the mor was crystallized 
 with the irreversible antagonist -fna 
 present in the binding site , a ligand 
 with significant structural similarity to buprenorphine .
-fna 
 is covalently bound to the side chain nitrogen of lys233 ( figure 3 ) .
the docked 1n structure approximately 
 overlays -fna but , without the covalent restraint , lies a little 
 deeper in the binding site .
there is a hydrogen bond between the positively 
 charged nitrogen and the side chain of asp147 .
the cyclopropyl moiety 
 overlays that of -fna occupying , but not filling , a small pocket 
 formed by asn150 , trp293 , ile322 , and tyr326 .
the t - butyl group makes no specific interactions with the protein but 
 projects into the same large pocket occupied by the methyl ester of 
 -fna .
mor with the protein in green , the crystal structure ligand 
 ( -fna ) 
 in cyan , and the docked buprenorphine ( 1n ) in pink .
the 
 hydrogen bond between the docked ligand and asp147 is shown as the 
 black dashed line .
two ligands , the i - butyl ( 1b ) and i - pentyl 
 ( 1c ) analogues of buprenorphine ( 1n ) , were 
 selected for preliminary in vivo evaluation in the para - phenylquinone ( ppq ) abdominal 
 stretch assay ( table 3 ) . in this assay , ppq acts as a fairly low intensity nociceptive 
 stimulus such that even partial opioid agonists are active as antinociceptives . 
 these two ligands were chosen as they had the desired lower efficacy 
 partial agonist activity at mor in the [ s]gtps 
 assay coupled with higher efficacy at kor . as it is difficult to accurately 
 predict the in vivo profile of mixed - action ligands , one ligand ( 1b ) was chosen that was substantially biased toward kor , while 
 the other ( 1c ) had a more balanced profile . in the ppq 
 assay , 1b was a potent agonist ( ed50 0.02 
 mg / kg s.c . ) that could be reversed by norbni ( ad50 6.5 
 mg / kg s.c . ) but only partly reversed by -fna ( a maximum reversal 
 of 27% at the highest -fna dose ) ( table 3 ) .
compound 1c was equally potent ( 0.02 mg / kg s.c . ) 
 and again could be reversed by norbni ( ad50 2.45 mg / kg 
 s.c . ) and partially reversed by -fna ( 59% reversed at 10 g / brain 
 -fna ) .
as predicted , based on 
 earlier work by ourselves and others , the n - cyclopropylmethylnororvinols 
 synthesized and evaluated in this study had very high affinity but 
 little to no mor / kor selectivity in binding assays . also as predicted , 
 in the [ s]gtps assay used to determine the level 
 of agonist activity at each receptor , the majority of the ligands 
 were kor agonists with lower efficacy at the mor .
importantly , the 
 [ s]gtps data for the known compounds buprenorphine 
 ( 1n ) and m320 ( 5 ) were in agreement with 
 previously reported isolated tissue data and findings from in vivo 
 studies , with 1n displaying no efficacy at the kor , while 5 was a very potent , full agonist at this receptor , and both 
 displayed partial agonist activity at the mor such that 1n profiled as a mor partial agonist , kor antagonist and 5 as a high efficacy kor agonist with some mor activity .
similarly , evaluation of 1a in both [ s]gtps 
 and isolated tissue assays ( tables 1 and 2 ) gave results in good agreement , indicating low 
 efficacy at each receptor .
we have previously proposed that 
 kor agonist activity can be achieved 
 in orvinol and related series through interaction with either a region 
 above and away from c7 ( relating to the site occupied by the r - group 
 in series 1 and 3 ) or a region below c8 
 ( relating to the site occupied by the r - group in series 2 and 4 ) .
the results of the comfa analysis 
 performed on the compounds prepared for this study are in agreement 
 with this hypothesis . with all compounds held in their low energy 
 h - bonding conformation
, an excellent correlation was found between 
 predicted and actual kor efficacy and two regions , corresponding to 
 the two lipophilic sites just described , were highlighted as being 
 beneficial to kor efficacy ( figure 1 ) .
importantly , 
 this appears to confirm that the hydrogen bonded conformation of the 
 orvinols is preserved on interaction with the kor . in general , 
 the 2 and 3 alcohols having opposite relative 
 stereochemistry to buprenorphine ( series 2 and 4 ) display higher kor efficacy than series 1 and 3 , which have the same relative stereochemistry to buprenorphine . 

substantial differences in efficacy between series was also found 
 at the mor , with series 4 > series 1 > 
 series 2  series 3 . comparing the 
 buprenorphine - like 
 3 alcohols ( 1 ) with their diastereoisomers ( 2 ) ,
the results from the [ s]gtps assays 
 indicate that those having the same relative stereochemistry as buprenorphine 
 have equal or higher efficacy at mor than their diastereoisomers ( 2 ) but that 2 have higher efficacy at kor , often 
 substantially so .
this finding was replicated in the gpi assay where 
 buprenorphine ( 1n ) was found to be a mor partial agonist , 
 while its isomer ( 2i ) was a potent kor agonist . within 
 the 2 alcohols , those with the opposite relative stereochemistry 
 ( 4 ) to buprenorphine mostly had higher efficacy for both 
 mor and kor than their diastereoisomers ( 3 ) .
the 2 
 alcohols ( 3,4 ) were in general of higher 
 efficacy at both mor and kor than the 3 alcohols ( 1,2 ) . within tertiary alcohols ( 1 ) , 

kor efficacy was lowest 
 in those ligands having branching at c21 , while insertion of one or 
 two methylene units increased kor efficacy .
therefore , for example , 1a having an isopropyl group was a low efficacy partial agonist 
 ( 30% relative to u69,593 ) , whereas 1b and 1c ( isobutyl and isopentyl containing ) were higher efficacy agonists 
 ( 84% and 69% relative to u69,593 ) .
a similar increase in efficacy 
 on going from isopropyl to isobutyl and isopentyl was seen in the 
 diastereomeric series of tertiary alcohols ( 2a versus 2b and 2c ) , but efficacy at the kor was generally 
 higher for this series than for their diastereomers .
the isopropyl 
 group also led to lowest kor efficacy in both series of secondary 
 alcohols ( 3a and 4a ) , though in these series 
 other ligands having branching at c21 , for example , the cyclopentyl 
 in 3d and 4d had significantly higher efficacy . 
 these results are consistent with previous studies in isolated tissue 
 assays with 17-nme orvinols ( series 1 , but n - cyclopropylmethyl replaced by n - me ) where it was found that branching 
 of the alkyl group at the point of attachment to the carbinol function 
 ( i.e. , at c21 ) resulted in lower potency and efficacy at the mor , 
 while in general , mor and kor potency and efficacy increased with 
 increasing chain length .
the results of the 
 comfa study provide further support for these conclusions with the 
 region adjacent to c21 found to be detrimental to efficacy at the 
 kor ( figure 1 ) , appearing to confirm our hypothesis 
 that the loss of kor efficacy in 1n relative to closely 
 related orvinols is due to a methyl group of the t - butyl moiety interacting favorably with the antagonist conformation 
 of kor receptor and/or disfavoring the agonist conformation .
docking of 1n to the recently published crystal structures 
 of the kor confirms that the t - butyl group accesses 
 a large lipophilic region when the receptor is in an antagonist - bound 
 conformation but does not provide any more detailed information on 
 why buprenorphine is not an agonist at kor .
the modeling does shed 
 some light on why the n - cyclopropylmethyl group , 
 and related moieties such as allyl , helps confer substantial antagonist 
 character to the orvinols and other series ; groups of this size appear 
 to bind tightly to a pocket formed by val108 , asn141 , trp287 , and 
 tyr320 in the kor and asn150 , trp293 , ile322 , and tyr326 in the mor .
comparison of 5 and 1c suggests that 
 reducing the 6,14-bridge from etheno to ethano has little or no effect 
 on efficacy at mor but substantially decreases efficacy at kor .
previously , 
 it has been suggested that reduction of the bridge leads to some attenuation 
 of mor intrinsic activity , though this 
 conclusion was based on in vivo antinociceptive activity and without 
 the benefit of selective antagonists or of data from isolated tissue 
 assays .
the in vivo evaluation of 1b and 1c gave 
 results entirely in keeping with the in vitro analysis .
both had substantial 
 kor agonism with 1c having a greater mor component than 1b .
while there is no clear dose dependency found in the experiments 
 using -fna pretreatment , this may simply be indicative of the 
 low partial agonist character of these ligands at the mor , meaning 
 we are looking at inhibition in vivo of a group of receptors responsible 
 for only part of the activity ( analgesia ) that is the measured end - point . 

the current in vitro analysis also helps rationalize the in vivo data 
 that has been reported for a limited number of these compounds previously .
the in vivo data was collected on compounds 
 of type 1 with r groups from methyl to butyl ( including 
 branched isomers ) and suggested that compounds with r = n - propyl or larger ( up to t - butyl ) were mor partial 
 agonists that in some cases had high efficacy kor agonist activity .
the in vitro data generated for the compounds 
 common to these previous studies and the current work ( 1a , 1b , 1l , 1n ; r = i - propyl , i - butyl , n - propyl , 
 and t - butyl ) is mostly consistent with these findings 
 with low mor efficacy but variable kor efficacy that appears to initially 
 increase with the size of the r group ( e.g. , i - propyl 
  i - butyl , 30  84% ) before then decreasing 
 again ( i - butyl  t - butyl , 
 84  0% ) . the n - propyl analogue ( 1l )
was only evaluated in isolated tissue assays where it was found 
 to be of low efficacy agonist in guinea pig ileum ( gpi ) .
the difficulty in reversing the agonist effects of the ligands 
 in the gpi by selective antagonists for mor and kor ( ctap and norbni ) 
 makes commenting on the receptor selectivity of this activity difficult 
 but is typical of the orvinol series and results from their tight , 
 long - lived binding to the receptors and can be indicative of an extended 
 duration of action .
differences between the gpi and 
 the cell based [ s]gtps assays may be related to 
 the easier access to receptors in the cell homogenates .
the activity 
 of these compounds as antagonists in the mouse vas deferens ( mvd ) 
 suggested that all were partial , rather than full , agonists .
however , 
 in vivo 1l , having a n - propyl group , 
 appeared to have higher efficacy than the c20 branched chain analogues 1n ( t - butyl ) and 1a ( i - propyl ) , contrary to the gpi derived data just described .
the present study confirms the orvinols lack of selectivity 
 in binding to opioid receptors and that kor / mor agonists of varying 
 efficacy can be obtained from this series .
as predicted , efficacy 
 can be controlled by the chain length of the c20 r group and by the 
 introduction of branching or ring systems into the chain ; a full range 
 of profiles from ekc - like kor agonists / mor partial agonists ( e.g. , 1c , 1e ) , selective kor agonists ( e.g. , 3b , 3i , and 4a ) , nonselective agonists 
 ( e.g. , 1h and 4f ) , and even a ligand with 
 predominant mor activity ( 1j ) were seen .
preliminary 
 in vivo evaluation of 1b and 1c , coupled 
 with the known profiles of 1n and 5a , suggests 
 that the [ s]gtps data is predictive of the in 
 vivo activity of these ligands .
compounds have successfully been obtained 
 with the targeted profile of potent moderate to high efficacy kor 
 agonism combined with potent partial agonist activity at the mor .
reagents 
 and solvents were purchased from sigma - aldrich or alfa 
 aesar and used as received .
buprenorphine ( 1n ) was supplied 
 by the national institute on drug abuse , bethesda , maryland .
h and c nmr spectra were obtained with a bruker-400-mhz 
 instrument ( h at 400 mhz , c at 100 mhz ) ; 
  in ppm , j in hz with tms as an internal standard . 

column chromatography was performed using redisep prepacked columns 
 with a teledyne isco combiflash instrument .
ligands were tested as 
 their hydrochloride salts , prepared by adding 5 equivalents of hcl 
 ( 1 n solution in diethyl ether ) to a solution of compound in anhydrous 
 methanol .
all reactions were carried out under an inert atmosphere 
 of nitrogen unless otherwise indicated .
the grignard 
 reagents were prepared from the corresponding bromides ( 5 mmol ) by 
 reaction with magnesium ( 182 mg , 7.5 mmol ) in anhydrous thf ( 5 ml ) 
 containing a crystal of iodine .
the grignard reagents were titrated 
 prior to use by adding 1 ml of the grignard solution to a flask containing 
 1,10-phenanthroline ( 2 mg ) in anhydrous thf ( 2 ml ) ( purple 
 solution ) and titrating with 1 m 2-butanol ( anhydrous ) in thf ( end 
 point pale yellow solution ) .
a solution of the appropriate grignard 
 reagent ( 1 m in thf , 1.2 ml , 1.2 mmol ) was treated dropwise at room 
 temperature with a solution of n - cyclopropylmethyl-6,14-endo - ethanonorthevinone ( 8) ( 500 mg , 1.18 mmol ) 
 or n - cyclopropylmethyl-6,14-endo - ethanonorthevinal ( 10 ) ( 500 mg , 1.22 mmol ) in anhydrous 
 toluene ( 12 ml ) . after stirring at room temperature for 20 h ,
the 
 reaction was quenched by the addition of saturated aqueous ammonium 
 chloride solution ( 20 ml ) .
the combined organic phases were washed 
 with saturated aqueous sodium bicarbonate , dried over mgso4 , filtered , and evaporated in vacuo .
the residue was purified by 
 column chromatography over silica gel eluting with a gradient from 
 10% to 30% ethyl acetate in hexane .
rf values are recorded from tlc eluted with 30:1:69 ethyl acetate / ammonia 
 solution / hexane .
a solution of the appropriate thevinol 
 ( 0.25 mmol ) in anhydrous hmpa ( 1 ml ) under an inert atmosphere was 
 treated with sodium hydride ( 21 mg , 0.875 mmol ) followed by 1-propanethiol 
 ( 79 l , 0.875 mmol ) .
after the addition was complete , the reaction 
 mixture was heated to 120 c and stirred for 3 h. on cooling 
 to room temperature , nh4cl ( sat , aq ) was added and the 
 mixture extracted with diethyl ether .
the organic phase was dried ( mgso4 ) , filtered , and evaporated to dryness .
the hcl salts were 
 prepared by the addition of 2 m hcl in diethyl ether ( 1.2 equiv ) to 
 a solution of the orvinol in diethyl ether . the white precipitate 
 that formed was collected by filtration , washed with ether , and dried 
 under high vacuum .
a solution of the ketone ( 0.215 mmol ) in anhydrous 
 thf ( 7 ml ) was 
 added dropwise to a suspension of lialh4 ( 20.5 mg , 0.54 
 mmol ) in thf at room temperature .
the resulting mixture was allowed 
 to stir for 1 h and then treated carefully with saturated aqueous 
 sodium sulfate sulfate solution until all aluminum salts had precipitated . 

the filtrate was dried over mgso4 , evaporated 
 to dryness , and the residue purified by column chromatography over 
 silica gel ( 30% ethyl acetate and 0.5% nh4oh in hexane ) .
a solution of 
 dmso ( 170 l , 2.4 mmol ) in anhydrous dcm ( 5 ml ) was added dropwise 
 to a solution of oxalyl chloride ( 93 l , 1.1 mmol ) in dcm ( 2 
 ml ) at 78 c .
the resulting solution was stirred at 78 
 c for 10 min and then treated dropwise with a solution of the 
 alcohol ( 1 mmol ) in dcm ( 5 ml ) .
the reaction was stirred for a further 
 15 min before triethylamine ( 0.7 ml , 5 mmol ) was added slowly and 
 the resulting solution allowed to warm to room temperature .
water 
 ( 10 ml ) was added and the resulting mixture stirred for 10 min .
the 
 combined organic extracts were washed with saturated ammonium chloride , 
 dried over mgso4 , filtered , and the solvent removed under 
 reduced pressure .
the residue was purified by column chromatography 
 over silica gel ( 0.5% nh4oh , 30% ethyl acetate in hexane ) 
 to afford the product . using general procedure
a on 8 , with isopentyl magnesium bromide , 9c was isolated 
 as a white solid ( 216 mg , 37% ) .
h nmr ( 400 mhz , cdcl3 )  0.080.12 ( 2h , m ) , 0.440.52 ( 2h , 
 m ) , 0.700.83 ( 2h , m ) , 0.91 ( 3h , d ) , 0.93 ( 3h , d ) , 1.011.08 
 ( 2h , m ) , 1.191.56 ( 5h , m ) , 1.34 ( 3h , s ) , 1.66 ( 1h , dd ) , 1.741.85 
 ( 2h , m ) , 1.902.03 ( 2h , m ) , 2.192.38 ( 4h , m ) , 2.64 
 ( 1h , dd ) , 2.792.86 ( 1h , m ) , 2.953.01 ( 2h , m ) , 3.54 
 ( 3h , s ) , 3.88 ( 3h , s ) , 4.42 ( 1h , s ) , 5.10 ( 1h , s ) , 6.54 ( 1h , d ) , 6.70 
 ( 1h , d ) . hrms ( esi ) calcd for c31h46no4 ( mh ) , 496.3421 ; found , 496.3414 ( 100% ) . using general procedure
b with 9c ( 50 mg ) gave 1c as a yellow solid ( 47 mg , 98% ) h nmr ( 400 mhz , cdcl3 )  0.080.12 
 ( 2h , m ) , 0.460.50 ( 2h , m ) , 0.700.83 ( 2h , m ) , 0.91 
 ( 6h , d ) , 1.001.08 ( 2h , m ) , 1.191.26 ( 1h , m ) , 1.34 
 ( 3h , s ) , 1.341.54 ( 4h , m ) , 1.651.69 ( 1h , m ) , 1.771.81 
 ( 2h , m ) , 1.902.03 ( 2h , m ) , 2.182.38 ( 4h , m ) , 2.66 
 ( 1h , dd ) , 2.792.86 ( 1h , m ) , 2.953.00 ( 2h , m ) , 3.52 
 ( 3h , s ) , 4.42 ( 1h , s ) , 5.16 ( 1h br s ) , 6.50 ( 1h , d , j = 8.0 hz ) , 6.69 ( 1h , d ) .
hrms ( esi ) calcd for c30h44no4 ( mh ) , 482.3265 ; 
 found , 482.3241 ( 100% ) ; anal .
( c30h43no4hcl1.5h2o ) c , h , n. using general procedure a on 10 with cyclohexylmethylmagnesium 
 bromide gave 11a , isolated as a white solid , 89% .
h nmr ( 400 mhz , cdcl3 )  0.090.10 
 ( 2h , m ) , 0.460.50 ( 2h , m ) , 0.680.72 ( 1h , m ) , 0.780.89 
 ( 3h , m ) , 0.950.98 ( 1h , m ) , 1.131.28 ( 5h , m ) , 1.471.53 
 ( 4h , m ) , 1.631.71 ( 8h , m ) , 1.831.86 ( 1h , m ) , 2.002.02 
 ( 2h , m ) , 2.212.29 ( 3h , m ) , 2.322.42 ( 1h , m ) , 2.582.66 
 ( 2h , m ) ,
2.953.00 ( 1h , d ) , 3.063.08 ( 1h , d ) , 3.41 
 ( 1h , s ) , 3.86 ( 3h , s ) , 4.41 ( 1h , s ) , 6.53 ( 1h , d ) , 6.68 ( 1h , d ) ; hrms 
 ( esi ) calcd for c32h46no4 ( mh ) , 508.34 ; found , 508.34 . using general procedure 
 d on 11a ( r = cyclohexylmethyl ) gave 12 ( r 
 = cyclohexylmethyl ) as a white solid ( 80 mg , 32% ) .
h nmr 
 ( 400 mhz , cdcl3 )  0.070.08 ( 2h , m ) , 0.450.49 
 ( 2h , m ) , 0.680.78 ( 2h , m ) , 0.840.95 ( 2h , m ) , 1.121.16 
 ( 1h , m ) , 1.221.35 ( 4h , m ) , 1.501.51 ( 1h , m ) , 1.54 
 ( 3h , s ) , 1.581.68 ( 5h , m ) , 1.831.85 ( 1h , m ) , 1.902.00 
 ( 1h , m ) , 2.262.35 ( 3h , m ) , 2.372.38 ( 1h , d ) , 2.472.53 
 ( 1h , dd ) , 2.592.63 ( 1h , m ) , 2.662.73 ( 1h , m ) , 2.942.99 
 ( 2h , m ) ,
3.043.06 ( 1h , d ) , 3.39 ( 1h , s ) , 3.86 ( 3h , s ) , 4.44 
 ( 1h , s ) , 6.54 ( 1h , d ) , 6.69 ( 1h , d ) ; hrms ( esi ) calcd 
 for c32h44no4 ( mh ) , 506.33 ; 
 found , 506.33 . using procedure a 
 for the addition of methylmagnesium bromide to 12 ( r 
 = cyclohexylmethyl ) , 13 ( r = cyclohexylmethyl )
h nmr ( 400 mhz , cdcl3 )  0.080.10 ( 2h , m ) , 0.470.50 ( 2h , 
 m ) , 0.690.72 ( 2h , m ) , 0.900.99 ( 2h , m ) , 1.041.10 
 ( 2h , m ) , 1.15 ( 3h , s ) , 1.201.28 ( 3h , m ) , 1.56168 
 ( 8h , m ) , 1.741.77 ( 2h , m ) , 1.85 ( 1h , m ) , 1.992.03 
 ( 2h , m ) , 2.182.24 ( 2h , m ) , 2.262.36 ( 1h , m ) ,
2.582.63 
 ( 1h , m ) , 2.782.86 ( 1h , m ) , 2.962.99 ( 1h , d ) , 2.992.03 
 ( 1h , d ) , 3.51 ( 1h , s ) , 3.87 ( 3h , s ) , 4.38 ( 1h , s ) , 4.68 ( 1h , s ) , 6.53 
 ( 1h , d ) , 6.69 ( 1h , d ) ; hrms ( esi ) calcd for c33h48no4 ( mh ) , 522.36 ; found , 522.36 . using general procedure b on 13 ( r = cyclohexylmethyl ) gave 2e as a white solid .
h nmr , 270 mhz ( cdcl3 )  0.070.11 
 ( 2h , m ) , 0.460.50 ( 2h , m ) , 0.670.81 ( 2h , m ) , 0.861.30 
 ( 10h , m ) , 1.551.89 ( 12h , m ) , 1.942.08 ( 2h , m ) , 2.142.26 
 ( 3h , m ) , 2.342.41 ( 1h , m ) , 2.55 ( 1h , dd ) , 2.762.86 
 ( 1h , m ) , 2.92 ( 1h , d ) , 2.99 ( 1h , d ) , 3.50 ( 3h , s ) , 4.40 ( 1h , s ) , 4.71 
 ( 1h , s ) , 6.48 ( 1h , d ) , 6.66 ( 1h , d ) ; hrms , m / z for ( c32h46no4 ) [ mh ] , calcd , 508.3427 ; found , 508.3424 . anal .
( c32h45no4hcl1.5h2o ) c , h , n. phenethylmagnesium bromide 
 addition to 10 using general procedure a gave 11a , isolated as a white solid ( 218 mg , 58% ) .
rf 0.48 : h nmr ( 400 mhz , cdcl3 )  
 0.080.10 ( 2h , m ) , 0.460.49 ( 2h , m ) , 0.720.96 
 ( 2h , m ) , 1.151.25 ( 3h , m ) , 1.511.66 ( 2h , m ) , 1.721.79 
 ( 4h , m ) , 1.902.03 ( 2h , m ) , 2.212.35 ( 4h , m ) , 2.622.69 
 ( 3h , m ) , 2.953.06 ( 2h , dd ) , 3.38 ( 3h , s ) , 3.86 ( 3h , s ) , 4.18 
 ( 1h , m ) , 4.40 ( 1h , s ) , 6.53 ( 1h , d ) , 6.68 ( 1h , d ) , 7.167.30 
 ( 5h , m ) ; hrms ( esi ) calcd for c33h42no4 ( mh ) , 516.31 ; found , 516.31 .
compound 11a , r = phenylethyl ( 0.36 mmmol ) was treated as described in general 
 procedure d. the residue was purified by column chromatography using 
 a combi flash machine ( 30% ethyl acetate in hexane ) to afford 12 ( r = phenethyl ) .
rf 0.55 : h nmr ( 400 mhz , cdcl3 )  0.070.09 ( 2h , d ) , 0.440.49 ( 2h , 
 m ) , 0.730.76 ( 1h , m ) , 1.151.32 ( 2h , m ) , 1.531.57 
 ( 1h , m ) , 1.561.71 ( 2h , m ) , 1.992.03 ( 2h , m ) , 2.232.32 
 ( 4h , m ) , 2.592.60 ( 1h , m ) , 2.702.78 ( 2h ,
m ) , 2.893.08 
 ( 5h , m ) , 3.37 ( 3h , s ) , 3.86 ( 3h , s ) , 4.43 ( 1h , s ) , 6.54 ( 1h , d ) , 6.68 
 ( 1h , d ) , 7.147.24 ( 5h , m ) ; hrms ( esi ) calcd for 
 c33h40no4 ( mh ) , 514.30 ; 
 found , 514.30 .
compound 12 ( r = phenylethyl ) ( 100.0 mg , 0.19 mmol ) was treated as described 
 in general procedure c to give 11b ( r = phenethyl )
h nmr ( 400 mhz , cdcl3 )  0.070.09 
 ( 2h , m ) , 0.470.49 ( 2h , m ) , 0.720.80 ( 2h , m ) , 0.870.99 
 ( 2h , m ) , 1.591.82 ( 5h , m ) , 1.962.04 ( 2h , m ) , 2.182.34 
 ( 5h , m ) , 2.612.72 ( 2h , m ) , 2.742.82 ( 1h , m ) , 2.922.99 
 ( 3h , m ) , 3.54 ( 3h , s ) , 3.87 ( 3h , s ) , 4.474.48 ( 1h , d ) , 5.46 
 ( 1h , s ) , 6.54 ( 1h , d ) , 6.70 ( 1h , d ) , 7.157.18 ( 1h , m ) , 7.247.28 
 ( 4h , m ) ; hrms ( esi ) calcd for c33h42no4 ( mh ) , 516.31 ; found , 516.31 .
( r = phenylethyl ) 
 ( 54 0.0 mg , 0.10 mmol ) was treated as described in general procedure 
 b to give 3i .
rf 0.14 ; h nmr , 270 
 mhz ( cdcl3 )  0.060.09 ( 2h , m ) , 0.450.50 
 ( 2h , m ) , 0.640.80 ( 2h , m ) , 0.820.98 ( 2h , m ) , 1.581.86 
 ( 5h , m ) , 1.912.08 ( 2h , m ) , 2.132.32 ( 4h , m ) , 2.602.84 
 ( 3h , m ) , 2.913.03 ( 3h , m ) , 3.50 ( 3h , s ) , 3.81 ( 1h , t ) , 4.49 
 ( 1h , s ) , 5.45 ( 1h , s ) , 6.48 ( 1h , d ) , 6.67 ( 1h , d ) , 7.137.32 
 ( 5h , m ) ; hrms , m / z for ( c32h40no4 ) [ mh ] , calcd , 502.2957 ; 
 found , 502.2956 .
( c32h39no4hcl1.5h2o ) c , h , n. compound 11a ( r = phenethyl ) 
 was treated as described in general procedure b to give 4k .
h nmr ( 400 mhz , cdcl3 )  0.080.09 
 ( 2h , m ) , 0.450.50 ( 2h , m ) , 0.66 ( 1h , m ) , 079 ( 1h , m ) , 1.121.13 
 ( 1h , m ) , 1.391.48 ( 1h , m ) , 1.521.57 ( 2h , m ) , 1.631.67 
 ( 1h , d ) , 1.701.80 ( 4h , m ) , 1.901.99 ( 3h , m ) , 2.192.38 
 ( 5h , m ) , 2.602.70 ( 3h , m ) , 2.85 ( 1h , m ) , 2.932.98 
 ( 1h , d ) , 3.043.05 ( 1h , d ) , 3.35 ( 3h , s ) , 4.41 ( 1h , s ) , 6.49 
 ( 1h , d ) , 6.67 ( 1h , d ) , 7.16 ( 1h , m ) , 7.167.30 ( 5h , m ) ; hrms 
 ( esi ) calcd for c32h40no4 ( mh ) , 502.2957 ; found , 502.3002
( c32h39no4.hcl.0.5h2o ) c , h , n. comfa : all of the modeling was carried 
 out using the sybyl - x 1.0 molecular modeling environment from tripos 
 inc .
the comfa analysis 
 was carried out as per the instructions in the sybyl - x 1.0 documentation . 

docking : the 4djh crystal structure of the kor and the 4dkl crystal 
 structure of the mor were prepared for docking work by running them 
 through the protein preparation wizard tool of the schrdinger 
 software .
the binding site was defined as a sphere of 5 
  radius centered on the centroid of the crystal structure ligand 
 with the requirement that the centroid of the docked ligand lies within 
 this sphere .
 dual - acting kappa opioid receptor 
 ( kor ) agonist and mu opioid receptor 
 ( mor ) partial agonist ligands have been put forward as potential treatment 
 agents for cocaine and other psychostimulant abuse . 
 members of the 
 orvinol series of ligands are known for their high binding affinity 
 to both kor and mor , but efficacy at the individual receptors has 
 not been thoroughly evaluated . in this study 
 , it is shown that a predictive 
 model for efficacy at kor can be derived , with efficacy being controlled 
 by the length of the group attached to c20 and by the introduction 
 of branching into the side chain . 
 in vivo evaluation of two ligands 
 with the desired in vitro profile confirms both display kor , and to 
 a lesser extent mor , activity in an analgesic assay suggesting that , 
 in this series , in vitro measures of efficacy using the [ 35s]gtps assay are predictive of the in vivo profile . 
Introduction
Synthesis
Results
Discussion
Conclusions
Experimental Section