SYNTHESIS, CHARACTERIZATION, AND BIOLOGICAL EVALUATION OF A NOVEL CLASS OF N-(ARYLETHYL)-N-ALKYL-2-(1-PYRROLIDINYL)ETHYLAMINES - STRUCTURAL REQUIREMENTS AND BINDING-AFFINITY AT THE SIGMA-RECEPTOR

By synthesizing and testing a part-structure, N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine (3), derived from our previously reported high affinity sigma-receptor ligands (1S,2R)-(-)-N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)cyclohexylamine [(-)-2] and (+)-2, we have identified a novel class of superpotent (subnanomolar affinity) sigma-ligands specific for the a receptor labeled by [H-3]-(+)-3-PPP. When 3 was tested for its capacity to displace [H-3]-(+)-3-PPP from guinea pig brain membranes, it exhibited a K(i) of 0.34 nM, which is better than either of its parent compounds (-)-2 (K(i) = 1.3 nM) and (+)-2 (K(i) = 6.0 nM). Other compounds related to 3 such as N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-homopiperidinyl)ethylamine (19) exhibited K(i) = 0.17 nM ([H-3]-(+)-3-PPP). The determinants for high sigma-receptor affinity of 3 were examined by manipulation of this structure in a number of different ways. The high efficacy of these compounds for the sigma-receptor, their relative chemical simplicity and ease of synthesis, and their high degree of selectivity identifies N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine (3) and related compounds as a highly promising base for determination of the functional role of sigma-receptors as well as the development of novel therapeutic agents.