SYNTHESIS OF (1',2'-TRANS)-3-PHENYL-1-[2'-(N-PYRROLIDINYL)CYCLOHEXYL]-PYRROLID-2-ONES AS K-SELECTIVE OPIATES

(1′, 2′‐trans)‐3‐Phenyl‐1‐[2′‐(N‐pyrrolidinyl)cyclohexyl]‐pyrrolid‐2‐ones (1 and 2) and their 3, 4‐dichlorophenyl analogues (4 and 5) were synthesized as lactam analogues of U‐50, 488 (I; a κ‐opiate analgesic developed by Upjohn Company). Compounds 1 and 2 were found to be oxidized by air, in the presence of a strong base, to the 3‐hydroxylated derivative 3. Compound 4 gave slightly higher κ‐affinity (Ki = 10 nM) than I, with about half the κ‐selectivity (μ/κ = 23). Compounds 1 and 3 showed weaker κ‐binding (Ki = 400 nM), with about the same κ‐selectivity as 4. Compound 5, a diastereomer of 4, gave significantly weaker and less selective κ‐binding than 4; likewise, 2 is a weaker and less selective κ‐binder than 1. The binding data of intermediate compounds having the basic skeleton of I seem to reflect the importance of lipophilicity and the detrimental effects of bulky substituents on the amide nitrogen. It is likely that the binding conformation of I at the opiate receptors approaches that of the lactam analogue 4. Copyright © 1990 Wiley‐Liss, Inc., A Wiley Company