Synthesis and Biological Evaluation of Conformationally Restricted 2-(1-pyrrolidinyl)-N-[2-(3,4-dichlorophenyl)ethyl]-N-methylethylenediam Ines as Sigma Receptor Ligands. 1. Pyrrolidine, Piperidine, Homopiperidine, and Tetrahydroisoquinoline Classes

J Med Chem. 1992 Nov 13;35(23):4334-43. doi: 10.1021/jm00101a011.

Abstract

The synthesis and sigma receptor affinity of a series of conformationally restricted derivatives of 2-(1-pyrrolidinyl)-N-[2-(3,4-dichlorophenyl)ethyl]-N-methylethylenedi amine (1) is described. The pyrrolidinyl (or N,N-dialkyl),ethylenediamine,N-alkyl, and phenylethyl portions of this sigma receptor pharmacophore were restricted by its incorporation into 1,2-cyclohexanediamine-, pyrrolidine-, piperidine-, homopiperidine-, and tetrahydroisoquinoline-containing ligands. The sigma receptor binding affinities of these compounds were determined using [3H](+)-pentazocine in guinea pig brain homogenates. The synthesis of all but one class was achieved by acylation and alane reduction of the appropriate diamine precursors whose synthesis is also reported. sigma receptor affinities ranged from 1.34 nM for 6,7-dichloro-2-[2-(1-pyrrolidinyl)ethyl]tetrahydroisoquinoline (12) to 455 nM for (1R,2R)-trans-N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2- (1-pyrrolidinyl)cyclohexylamine [(-)-4]. In this displacement assay, (+)-pentazocine exhibited a Ki of 3.1 nM while DTG and haloperidol showed Ki values of 27.7 and 3.7 nM, respectively. The conformationally free parent compound 1 exhibited a Ki value of 2.1 nM. Comparison of both the sigma receptor affinities and nitrogen atom geometry of the compounds revealed that a gauche relation of the nitrogen atoms of cis-1,2-cyclohexanediamines is not imperative for high affinity as we had previously thought. It is highly likely that nitrogen lone pair orientations and steric factors on the aliphatic portions of these ligands play a major role in the sigma receptor binding of this pharmacophore.

Publication types

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

MeSH terms

  • Animals
  • Ethylenediamines / chemical synthesis*
  • Ethylenediamines / pharmacology
  • Guinea Pigs
  • Isoquinolines / chemical synthesis*
  • Isoquinolines / pharmacology
  • Molecular Conformation
  • Piperidines / chemical synthesis*
  • Piperidines / pharmacology
  • Pyrrolidines / chemical synthesis*
  • Pyrrolidines / pharmacology
  • Receptors, sigma / drug effects*
  • Receptors, sigma / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Ethylenediamines
  • Isoquinolines
  • Piperidines
  • Pyrrolidines
  • Receptors, sigma