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

J Med Chem. 1992 Jan;35(1):38-47. 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 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 sigma 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 Ki of 0.34 nM, which is better than either of its parent compounds (-)-2 (Ki = 1.3 nM) and (+)-2 (Ki = 6.0 nM). Other compounds related to 3 such as N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-homopiperidinyl)ethy lamine (19) exhibited Ki = 0.17 nM [( 3H]-(+)-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 selective 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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Ethylamines / chemical synthesis*
  • Ethylamines / chemistry
  • Ethylamines / metabolism
  • Guinea Pigs
  • Male
  • Pyrrolidines / chemical synthesis*
  • Pyrrolidines / chemistry
  • Pyrrolidines / metabolism
  • Rats
  • Rats, Inbred Strains
  • Receptors, Opioid / metabolism*
  • Receptors, sigma
  • Structure-Activity Relationship


  • Ethylamines
  • Pyrrolidines
  • Receptors, Opioid
  • Receptors, sigma