Journal of Medicinal Chemistry p. 1620 - 1626 (1989)
Update date:2022-08-04
Topics:
Halfpenny
Hill
Horwell
Hughes
Hunter
Johnson
Rees
This paper describes the chemical synthesis and the development of structure-activity relationships (SAR) for the κ opioid receptor affinity and μ/κ 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 κ selective agonist, PD117302 (trans-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzo[b]thiophene-4-act etamide) (1). The κ and μ opioid receptor binding affinities of 23 novel compounds are reported. It is observed that optimal μ/κ 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 μ/κ selectivity compared to the unsubstituted compound, e.g. compound 14, trans-(±)-N-methyl-N-[2-[3-(hydroxymethyl)-1-pyrrolidinyl]cyclo-hexylt ]-4-benzo[b]furanacetamide monohydrochloride, μ/κ receptor selectivity = 244. The cis fused, 4,5 dimethyl ether substituted cyclohexane analogue trans-(±)-N-methyl-N-[4,5-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-bent zo[b]thiophene-4-acetamide monohydrochloride (32) has high in vitro κ opioid receptor affinity (K(i) = 16 nM) and equipotent analgesic activity to morphine after iv administration in rats.
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