3H]DTG and [ 3H](+)-3-PPP label pharmacologically distinct σ binding sites in guinea pig brain membranes

Abstract

The interaction of various compounds with σ binding sites was examined in membranes prepared from whole guinea pig brain. Whereas [ 3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine labeled a single population of binding sites exhibiting a K d of 43 nM, [ 3H]1,3-di-o-tolylguanidine bound to two sites having K ds of 35 and 212 nM, and to a greater maximum number of sites than [ 3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine. Haloperidol, 1,3-di-o-tolyguanidine, BMY 14802, and (−)-pentazocine each displayed nearly equal affinity for binding sites labeled by [ 3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine and [ 3H]1,3-di-o-tolylguanidine, whereas (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine was 3 times more potent in inhibiting [ 3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine than [ 3H]1,3-di-o-tolylguanidine binding. In contrast, (+)-SKF 10,047, (+)-cyclazocine and (+)-pentazocine exhibited more than 9-fold higher affinity for [ 3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine than [ 3H]1,3-di-o-tolylguanidine binding sites. Dextromethorphan was 15-fold more potent against [ 3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine than [ 3H]1,3-di-o-tolylguanidine, inhibited [ 3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine binding in a biphasic manner, and inhibited [ 3H]haloperidol and [ 3H](+)-SKF 10,047 binding with potencies similar to those obtained against [ 3H]1,3-di-o-tolylguanidine and [ 3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine, respectively. Phenytoin increased [ 3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine and [ 3H](+)-SKF 10,047 binding, but did not enhance [ 3H]1,3-di-o-tolylguanidine or [ 3H]haloperidol binding. However, the potency of dextromethorphan to inhibit [ 3H]1,3-di-o-tolylguanidine binding was increased in the presence of phenytoin. These findings suggest the existence of heterogeneous populations of σ binding sites in guinea pig brain membranes.