title: Enantiospecificity of kappa receptors: comparison of racemic compounds and active enantiomers in two novel series of kappa agonist analgesics.
abstract: Two novel series, Ia,b and IIa,b, of kappa opioid antinociceptive agents have recently been described. 2a,b,3a,b,c The biological activities of 16 racemic compounds and their corresponding (-) enantiomers are now compared in a battery of tests. Enantiomers of unsubstituted piperidines Ia were synthesized starting from S(-) pipecolic acid, whereas the enantiomerically pure substituted piperidines (Ib), tetrahydroisoquinolines (IIa), and thienopiperidines (IIb) were, in general, obtained after diastereomeric crystallization of the corresponding tartrate salts. The absolute stereochemistry of one representative enantiomer from series IIa was determined to be (1S) by X-ray crystallographic analysis. Antinociceptive activity in the mouse abdominal constriction and tail-flick tests following subcutaneous administration, and binding affinity for kappa and mu receptors, were found to reside predominantly in the (-) enantiomers. Consequently, racemic compounds showed approximately half potency of the corresponding enantiomers. This potency difference was less clear after oral administration presumably due to small differences in bioavailability of the two corresponding enantiomers. For compounds with some affinity also for mu receptors (Ki less than 1,000 nM), the kappa/mu selectivity was maintained within each enantiomeric pair, in contrast to results found for other kappa agonists.
authors.affiliation: Zambeletti Research Laboratories, Baranzate, Milan, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Colle
authors.forename: G D
authors.initials: GD
authors.lastname: Clarke
authors.forename: G
authors.initials: G
authors.lastname: Dondio
authors.forename: G
authors.initials: G
authors.lastname: Giardina
authors.forename: G
authors.initials: G
authors.lastname: Petrone
authors.forename: M
authors.initials: M
authors.lastname: Sbacchi
authors.forename: V
authors.initials: V
authors.lastname: Vecchietti
mesh_terms: D000700:Analgesics / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D007700:Kinetics; D051379:Mice; D011957:Receptors, Opioid / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu