In the peripheral nervous system, all internal organs innervated by the parasympathetic nervous system have muscarinic receptors. For example, the heart, gastrointestinal tract, the urinary bladder, the sweat glands, the lacrimal glands, the blood vessels, and the pupils are all innervated through muscarinic receptors. The central nervous system is also comprised of a complex network of muscarinic receptors, both pre- and postsynaptic.
It has recently been discovered that there are several classes of muscarinic receptors based on their selectivity for certain agonists and antagonists. Molecular biological studies of muscarinic cholinergic receptors (mAChRs) have raised the possibility of designing subtupe-specific agonists and antagonists. See Bonner, T. I.; Buckley, N. J.; Young, A. C.; Brann, M. R.; Science 1987, 237, 527 (hereinafter Bonner); and Peralta, E. G.; Winslow, J. W.; Ashkenazi, A.; Smith, D. H.; Ramachandran, J.; Capon, D. J.; Trends Pharm. Sci. Suppl.. 1988, 9, 6, which are specifically incorporated by reference herein.
Complications in defining the selectivity of muscarinic ligands have developed from recent studies of the classification, regional distribution, and second messenger coupling of mAChR subtypes. Two mAChR subtypes have been defined pharmacologically on the basis of their affinities for the non-classical antagonist pirenzepine. See Giacobini, E.; Becker, R.; Current Research in Alzheimer Therapy, Taylor & Francis, New York, 1988 (hereinafter Giacobini), which is specifically incorporated by reference herein. One muscarinic receptor subtype, the M.sub.1 AChRs, have a high-affinity for pirenzepine, whereas another muscarinic receptor subtype, the M.sub.2 AChRs, have a low-affinity. See Giacobini. Recent work in the cloning of human mAChRs has redefined the mAChR into five new structural classes, m.sub.1 AChR m.sub.5 AChR. See Bonner; Peralta, E. G., Winslow, J. W., Ashkenazi, A., Smith, D. H., Ramachandran, J., Capon, D. J., Trends Pharm. Sci. Suppl., 1988, 9, 6 (hereinafter Peralta, Trends); and Peralta, E. G.; Ashkenazi, A.; Winslow, J. W.; Smith, D. H.; Ramachandran, J.; Capon, D. J.; EMBO J. 1987, 6,3923, Bonner, T. I.; Young, A. C.; Brann, M. R.; Buckley, N. J.; Neuron 1988, 1,403, which are all incorporated by reference herein. Pharmacologically, the m.sub.1 - and m.sub.4 AChR demonstrate a high affinity for pirenzepine, m.sub.3 -- and m.sub.5 AChR have intermediate affinity, and the m.sub.2 AChR has low affinity. See Peralta, Trends. By way of background, there has been confusion concerning the nomenclature used to describe MAChRs. The nomenclature of Peralta is used throughout, which differs from that of Bonner for the m.sub.3 and m.sub.4 AChR, i.e. their nomenclature for these two receptors are reversed.
Recently, these subclasses of mAChRs have been defined according to their functional correlation to second messenger systems. Muscarinic receptors are known to be coupled to phosphatidylinositol (PI) turnover, adenylate cyclase, and potassium channels. See Gil, D. W.; Wolfe, B. B.; J. Pharmacol. Exp. Ther. 1985, 232, 608; and Yatani, A.; Codina, J.; Brown, A. M.; Birnbaumer, L. Science 1987, 235, 207. The m.sub.1 -, m.sub.4 -, and m.sub.5 AChRs have been shown to couple exclusively to PI turnover, whereas m.sub.2 - and m.sub.3 AChRs couple only to adenylate cyclase inhibition. See Peralta, E. G., Ashkenazi, A., Winslow, J. W., Ramachandran, J., Capon, D. J., Nature, 1988, 334, 434, which is specifically incorporated by reference herein.
It is believed that muscarinic agonists and antagonists that are specific for a muscarinic receptor subtype could have substantial therepeutic benefits. For example, considerable research has been devoted to studying the therapeutic benefits of central muscarinic agonists in the treatment of senile dementia of the Alzheimer's type. See Giacobini and Davidson, M., Haroutunian, V., Mohs, R. C., Davis, B. M., Horvath, T. B., Davis, K. L.; Alzheimer's and Parkinson's Diseases: Strategies for Research and Development, Plenum, New York, 1986, 531-537 (hereinafter Davidson), which is specifically incorporated by reference herein. Currently available therapeutic cholinergic agents suffer from serious side effects, toxicity, and narrow therepeutic windows. See Bonner and Davidson. It is believed that agonists and antagonists that are specific for muscarinic receptor subtypes would be devoid of many of these side effects.
The development of potent selective receptor ligands using the "functionalized-congener" approach to drug design has been successfully established in the field of adenosine receptor ligands and catecholamines. See Jacobson, K. A.; Kirk, K. L.; Padgett, W. L.; Daly, J. W.; J. Med. Chem. 1985, 28, 1334; Jacobson, K. A.; Kirk, K. L.; Padgett, W. L.; Daly, J. W.; J. Med. Chem. 1985, 28, 1341; and Jacobson, K. A.; Marr-Leisy, D.; Rosenkranz, R. P.; Verlander, M. S.; Melmon, K. L.; Goodman, M.; J. Med. Chem. 1983, 26, 429, which are specifically incorporated by reference herein. By this approach, a chain terminating in a functional group (eg., an amine or carboxylic acid) is appended to a known receptor ligand at a site which allows modification with retention of biological activity. The chain-extended functional group may enhance receptor affinity and selectivity, and serves as a site for further functionalization to develop irreversible inhibitors, prodrugs, or labeled receptor probes. See Jacobson, K. A.; In Receptor Biochemistry and Methodology, (Venter, J. C.; Harrison, L. C., Eds.) Vol. II Adenosine Receptors; Cooper, D. M. F.; Londos, C., Eds.; Alan R. Liss: New York, 1988; pp 1-26, which is specifically incorporated by reference herein. This drug design approach may be applicable to other receptor ligands, in particular, muscarinic agents.
Many muscarinic agents contain an N-(4-amino-2-butynyl)amide substructure, most notably, oxotremorine, ##STR3## a potent and moderately selective central muscarinic agonist. See Noronha-Blob, L.; Canning, B.; Costello, D.; Kinnier, W. J.; Eur. J. Pharmacol. 1988, 154, 161; Bebbington, A.; Brimblecombe, R. W.; Shakeshaft, D.; Brit. J. Pharmacol. 1966, 26, 56; Bebbington, A.; Brimblecombe, R. W.; Rowsell, D. G.; Brit. J. Pharmacol. 1966, 26, 68; Neumeyer, J. L.; Moyer, U. V.; Richman, J. A.; Rosenberg, F. J.; Teiger, D. G.; J. Med. Chem. 1967, 10, 615; and Ringdahl, B.; Jenden, J.; Life Sci. 1983, 32, 2401; which are specifically incorporated by reference herein. While modification of either end of the linear central chain often has profound effects on biological activity, an open-ring analogue of oxotremorine, UH 5, ##STR4## maintains agonist activity and is nearly equi-potent to oxotremorine. Related to UH 5, BM 5, ##STR5## is also a potent muscarinic agent with presynaptic antagonist and postsynaptic agonist activity. See Nordstrom, O., Unden, A.; Grimm, V.; Frieder, B.; Ladinsky, H.; Bartfai, T.; In Dynamics of Cholinergic Function; Hanin, I., Ed.; Plenum: New York; 1983, pp 405-413; which is specifically incorporated by reference herein. This pharmacological profile is reported to be ideal for the putative treatment of Alzheimers dementia. See Hershenson, F. M.; Moos, W. H.; J. Med. Chem. 1986, 29, 1125; which is specifically incorporated by reference herein.