THE PERIPHERALLY ACTING KAPPA-OPIATE AGONIST EMD-61753 AND ANALOGS - OPIOID ACTIVITY VERSUS PERIPHERAL SELECTIVITY

EMD 61753 roxypyrrolidin-1-yl)-ethyl]-2,2-diphenyl-acetamide hydrochlo ride) is a peripherally selective kappa-opiate agonist, it exhibits an tihyperalgesic activity in animal models of inflammatory pain at doses which do not cause signs of central action. The structure of this com pound was varied in different ways and the resulting derivatives were tested for affinity to the kappa-receptor. Furthermore, those compound s with binding values comparable to that of EMD 61753 were tested for central activity. This was done by measuring the extent to which the h aloperidol-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 a nalogues or reference compounds tested is superior to the parent compo und with regard to its favourable ratio between kappa-receptor affinit y and peripheral selectivity.