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 σ receptor

Article abstract of DOI:10.1021/jm00079a004

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 σ 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) σ ligands specific for the σ receptor labeled by [³H]-(+)-3-PPP. When 3 was tested for its capacity to displace [³H]-(+)-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 ([³H]- (+)-3-PPP). The determinants for high σ 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 σ 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 σ receptors as well as the development of novel therapeutic agents.