title: The design of novel muscarinic partial agonists that have functional selectivity in pharmacological preparations in vitro and reduced side-effect profile in vivo.
abstract: Antagonist/agonist binding ratios (NMS/Oxo-M ratio) were used as an index of the efficacy of novel compounds acting at muscarinic receptors. These binding ratios have been used with a range of functional pharmacological assays to investigate the effects of varying the efficacy of muscarinic agonists. This strategy has been used as a means of obtaining functional receptor selectivity by exploiting differences in effective receptor reserves. The oxadiazole and pyrazine muscarinic agonists L-670,548 (NMS/Oxo-M ratio 1100) and L-680,648 (NMS/Oxo-M ratio 690) are amongst some of the most potent and efficacious agonists known. Decreasing the efficacy of compounds from these series, resulted in compounds with functional selectivity. The chloropyrazine L-689,660 (NMS/Oxo-M ratio 28) was an agonist on the rat superior cervical ganglion (M1), a partial agonist on the guinea-pig ileum (M3), but was an antagonist in the guinea-pig atria (M2). Synthesis of compounds with even lower predicted efficacy, such as the cyclopropyloxadiazole L-687,306 (NMS/Oxo-M ratio 15), maintained agonist activity in the ganglion, but showed antagonist activity in the M3 ileal, as well as the M2 atrial preparations. When tested in vivo these compounds did not produce many of the side effects associated with more efficacious agonists, particularly those associated with the cardiovascular system. However, they were active in reversing scopolamine-induced deficits in a variety of behavioural paradigms. This approach shows how functional selectivity for muscarinic receptor subtypes can be achieved in vitro, that in vivo reduces the dose-limiting side effects normally associated with muscarinic agonists.
authors.affiliation: Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, Great Britain.
authors.forename: S B
authors.initials: SB
authors.lastname: Freedman
authors.forename: G R
authors.initials: GR
authors.lastname: Dawson
authors.forename: L L
authors.initials: LL
authors.lastname: Iversen
authors.forename: R
authors.initials: R
authors.lastname: Baker
authors.forename: R J
authors.initials: RJ
authors.lastname: Hargreaves
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D015195:Drug Design; D005728:Ganglia, Sympathetic / Q000187:drug effects; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D007082:Ileum / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D010277:Parasympathomimetics / Q000494:pharmacology*; D051381:Rats; D011976:Receptors, Muscarinic / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D010277:Parasympathomimetics; D011976:Receptors, Muscarinic