σ2 Site-mediated inhibition of electrically evoked guinea pig ileum longitudinal muscle/myenteric plexus contractions

Abstract Functional and binding studies were performed in order to characterize the relative efficacy and affinity of a number of compounds that bind to σ sites. The ability of σ site ligands to inhibit electrically evoked contraction of the guinea pig ileum longitudinal muscle/myenteric plexus preparation was compared to the affinities of these compounds for σ 1 sites (assessed by displacement of [ 3 H](+)-pentazocine) and σ 2 sites (assessed by displacement of [ 3 H]1,3-di- o -tolylguanidine (DTG) in the presence of 5 μM dextromethorphan). It was shown that the rank order of potencies for suppression of electrically evoked contractions of guinea pig ileum perfectly matched the rank order of affinities of these compounds for the σ 2 binding site, while correlating poorly with the σ 1 binding site. In addition, no significant correlations were found between the efficacy of the tested compounds to inhibit contraction of the guinea pig ileum preparation and previously reported affinities for muscarinic, dopamine D 2 or MK-801 binding sites. Thus, the present study represents the first functional bioassay selectively sensitive to agents interacting with the σ 2 receptor subtype binding site, and provides a means with which to further elucidate the functional role of σ 2 sites.