KAPPA-OPIOID RECEPTOR-SELECTIVE AFFINITY LABELS - ELECTROPHILIC BENZENEACETAMIDES AS KAPPA-SELECTIVE OPIOID ANTAGONISTS

2-(3,4-Dichlorophenyl)-N-methyl-N-[1-(3- or 4-substituted phenyl)-2-(1 -pyrrolidinyl)ethyl]acetamides 3-6 were synthesized as kappa-selective affinity labels and evaluated for opioid activity. In smooth muscle p reparations, the non-electrophilic parent compound (+)-S-2 and the aff inity labels 3-6 behaved as kappa agonists in that they were potently antagonized by norbinaltorphimine (norBNI). In addition to the high bi nding affinity and selectivity of the 3-isothiocyanate 3 (DIPPA) to ka ppa opioid receptors, wash studies have suggested that this involves c ovalent binding. In the mouse tail-flick assay, the 3- and 4-substitut ed isomers (3 and 5, respectively) produced long-lasting antagonism of the antinociceptive effect of the kappa opioid agonist, N-methyl-N-[2 -(1-pyrrolidinyl)cyclohexyl]acetamide ((+/-)-U50,488). In contrast, th e non-electrophilic parent compound (+)-S-2 and the fumaramate derivat ive 4 were devoid of antagonist activity in the tail-flick assay. At s ubstantially different doses, DIPPA (3) and the 4-isothiocyanate 5 als o produced antinociception in the mouse abdominal stretch assay. In ad dition, DIPPA and the 3-fumaramate methyl ester 4 had improved in vivo kappa-selectivities compared to the unsubstituted parent compound (+) -S-2 and the para-substituted derivative 5. The improved kappa-selecti vities of 3 and 4 and the different agonist and antagonist potencies o f 3 and 5 may be explained respectively by the existence of multiple k appa agonist binding sites and distinct agonist and antagonist binding sites. In view of the antagonist selectivity and the apparent irrever sible binding of DIPPA to kappa receptors, it may serve as a useful ph armacologic or biochemical tool to investigate kappa opioid receptors.