The peripherally acting kappa-opiate agonist EMD 61753 and analogues: opioid activity versus peripheral selectivity

EMD 61753 (N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl) -ethyl ]- 2,2-diphenyl-acetamide hydrochloride) is a peripherally selective kappa-opiate agonist. It exhibits antihyperalgesic activity in animal models of inflammatory pain at doses which do not cause signs of central action. The structure of this compound was varied in different ways and the resulting derivatives were tested for affinity to the kappa-receptor. Furthermore, those compounds with binding values comparable to that of EMD 61753 were tested for central activity. This was done by measuring the extent to which the haloperidol-induced L-DOPA accumulation in the nucleus accumbens of the rat could be reversed after application of 10 mg/kg s.c. of the test compound. Structure-activity relationships revealed that none of the analogues or reference compounds tested is superior to the parent compound with regard to its favourable ratio between kappa-receptor affinity and peripheral selectivity.