INTERACTION OF 1,3-DI(2-(5-H-3 TOLYL) GUANIDINE WITH SIGMA-2 BINDING-SITES IN RAT-HEART MEMBRANE PREPARATIONS

Membrane preparations of rat hearts displayed specific binding activity for the prototypic-sigma (sigma) receptor ligand, 1,3-di(2-[5-H-3]tolyl) guanidine ([H-3]DTG), but not for the phencyclidine (PCP) receptor ligand, [H-3]MK-801. Scatchard plot analysis of [H-3]DTG binding revealed the presence of one high affinity saturable binding site with a K(D) of 8.7 nM and a B(max) of 100 pmol/g protein. The drug specificity profile of the receptor correlated with that of the sigma-receptor with the following order of potency: DTG > haloperidol > (-)-pentazocine > (-)-butaclamol > (+)-butaclamol > (-) SKF-10047 > (+)pentazocine > PCP > TCP > MK-801 > (+)SKF-10047. [H-3]DTG binding was sensitive to the Ca2+ channel blocker, verapamil (K(i) 202 nM) but not to the K+ channel blocker, 4-aminopyridine. The reverse stereoselectivity of [H-3]DTG binding for (-)-SKF-10047 and (-)-pentazocine (K(i) of 1289 and 140 nM as compared with 17582 and 2190 nM for (+)-SKF-10047 and (+)-pentazocine, respectively) indicated that the heart contains sigma-receptors with characteristics of the sigma-2 subtype.