7'-SUBSTITUTED AMINO-ACID CONJUGATES OF NALTRINDOLE - HYDROPHILIC GROUPS AS DETERMINANTS OF SELECTIVE ANTAGONISM OF DELTA(1) OPIOID RECEPTOR-MEDIATED ANTINOCICEPTION IN MICE

A series of amino acid conjugates (2-6) of naltrindole (1) were synthe sized from 7'-carboxynaltrindole (7) in order to obtain delta antagoni sts that would have minimal access to the central nervous system (CNS) upon peripheral administration. Ah of the ligands (2-7) were tested i n smooth muscle preparations and found to be potent and selective delt a opioid antagonists. Receptor binding showed 2-7 to be highly delta-s elective, with K-i ratios (mu/delta, kappa/delta) ranging from 127 to 38 000. Two of the more selective conjugates, the glycinate 2 and aspa rtate 3, were evaluated by the iv and icy routes in mice, and they aff orded very high iv/icv dose ratios (112 766 and 46 667, respectively) consistent with poor CNS penetration. The in vivo testing revealed tha t 2 and 3 are dr-selective antagonists, in contrast to naltriben and r elated ligands which are delta(2)-selective. The fact that the binding data are not consistent with the in vivo data suggests that the origi n of the selectivity of naltrindole congeners may be related to select ive access to tissue compartments in the CNS rather than to binding af finity differences between delta opioid receptor subtypes.