N-Methyl-N--1-phenylcyclopropanecarboxylic amides - analogs of U50488 with much reduced opiate affinity and loss of κ-selectivity

Article abstract of DOI:10.1016/0223-5234(91)90021-E

(+/-)-N-methyl-N--1-phenylcyclopropanecarboxylic amide (1) and its dichloro analog (2) were synthesized.Compounds 1 and 2 are related to the κ-selective opiate U-50488 in that the benzylic methylene moiety in U-50488 has been replaced by a cyclopropane ring.As compared to U-50488, a 600-fold reduction in kappa-affinity was observed with these 2 compounds; while the reduction in μ-affinity was less than 2-fold.Unlike U-50488, 1 and 2 also show measurable δ-binding.To explain the observed anomaly, the steric interaction between the N-methyl group and the cyclopropane ring and the tendency of the cyclopropane ring to conjugate with the neighboring phenyl group, both affecting the accessible conformations of the amide side chains of 1 and 2, are cosidered important factors.