SIGMA(2) SITE-MEDIATED INHIBITION OF ELECTRICALLY-EVOKED GUINEA-PIG ILEUM LONGITUDINAL MUSCLE MYENTERIC PLEXUS CONTRACTIONS

Functional and binding studies were performed in order to characterize the relative efficacy and affinity of a number of compounds that bind to sigma sites. The ability of sigma site ligands to inhibit electric ally evoked contraction of the guinea pig ileum longitudinal muscle/my enteric plexus preparation was compared to the affinities of these com pounds for sigma(1) sites (assessed by displacement of [H-3](+)-pentaz ocine) and sigma(2) sites (assessed by displacement of [H-3]1,3-di-o-t olylguanidine (DTG) in the presence of 5 mu M dextromethorphan). It wa s shown that the rank order of potencies for suppression of electrical ly evoked contractions of guinea pig ileum perfectly matched the rank order of affinities of these compounds for the sigma(2) binding site, while correlating poorly with the sigma(1) binding site. In addition, no significant correlations were found between the efficacy of the tes ted compounds to inhibit contraction of the guinea pig ileum preparati on and previously reported affinities for muscarinic, dopamine D-2 or MK-801 binding sites. Thus, the present study represents the first fun ctional bioassay selectively sensitive to agents interacting with the sigma(2) receptor subtype binding site, and provides a means with whic h to further elucidate the functional role of sigma(2) sites.