title: Highly selective kappa-opioid analgesics. 2. Synthesis and structure-activity relationships of novel N-[(2-aminocyclohexyl)aryl]acetamide derivatives.
abstract: This paper describes the chemical synthesis and the development of structure-activity relationships (SAR) for the kappa opioid receptor affinity and mu/kappa opioid receptor selectivity of novel N-[(2-aminocyclohexyl)aryl]acetamide derivatives. The SAR of this series are investigated by consideration of structural modifications made to the aromatic moiety, the amide linkage, and cyclohexane and the pyrrolidine ring substituents of the prototype kappa selective agonist, PD117302 (trans-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzo[b]thiophene-4- acetamide) (1). The kappa and mu opioid receptor binding affinities of 23 novel compounds are reported. It is observed that optimal mu/kappa receptor selectivity is obtained with a benzo[b]thiophene aromatic system attached via the C-4 position, which is discussed in terms of steric and electronic parameters. The amide linkage has been replaced with the reversed amide, an ester, an aminomethylene, a thioamide, and a secondary amide. The best of these isosteres is the N-methyl amide. Substitution of the pyrrolidine ring of PD117302 in the 3-position with a hydroxymethylene group increases the mu/kappa selectivity compared to the unsubstituted compound, e.g. compound 14, trans-(+/-)-N-methyl-N-[2-[3-(hydroxymethyl)-1-pyrrolidinyl] cyclohexyl]-4-benzo[b]furanacetamide monohydrochloride, mu/kappa receptor selectivity = 244. The cis fused, 4,5 dimethyl ether substituted cyclohexane analogue trans-(+/-)-N-methyl-N-[4,5-dimethoxy-2-(1-pyrrolidinyl) cyclohexyl]-benzo[b]thiophene-4-acetamide monohydrochloride (32) has high in vitro kappa opioid receptor affinity (Ki = 16 nM) and equipotent analgesic activity to morphine after iv administration in rats.
authors.affiliation: Parke-Davis Research Unit, Addenbrookes Hospital Site, Cambridge, U.K.
authors.forename: P R
authors.initials: PR
authors.lastname: Halfpenny
authors.forename: R G
authors.initials: RG
authors.lastname: Hill
authors.forename: D C
authors.initials: DC
authors.lastname: Horwell
authors.forename: J
authors.initials: J
authors.lastname: Hughes
authors.forename: J C
authors.initials: JC
authors.lastname: Hunter
authors.forename: S
authors.initials: S
authors.lastname: Johnson
authors.forename: D C
authors.initials: DC
authors.lastname: Rees
mesh_terms: D000701:Analgesics, Opioid / Q000138:chemical synthesis; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D008968:Molecular Conformation; D051381:Rats; D011957:Receptors, Opioid / Q000187:drug effects*; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D013329:Structure-Activity Relationship
chemical_list: D000701:Analgesics, Opioid; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu