Synthesis and Biological Evaluation of Conformationally Restricted 2-(1-Pyrrolidinyl)-N--N-methylethylenediamines as ? Receptor Ligands. 1. Pyrrolidine, Piperidine, Homopiperidine, and Tetrahydroisoquinoline Classes

Article abstract of DOI:10.1021/jm00101a011

The synthesis and ? receptor affinity of a series of conformationally restricted derivatives of 2-(1-pyrrolidinyl)-N-<2-(3,4-dichlorophenyl)ethyl>-N-methylethylenediamine (1) is described.The pyrrolidinyl (or N,N-dialkyl), ethylenediamine, N-alkyl, and phenylethyl portions of this ? receptor pharmacophore were restricted by its incorporation into 1,2-cyclohexanediamine-, pyrrolidine-, piperidine-, homopiperidine-, and tetrahydroisoquinoline-containing ligands.The ? 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. ? 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 K_i of 3.1 nM while DTG and haloperidol showed K_i values of 27.7 and 3.7 nM, respectively.The conformationally free parent compound 1 exhibited a K_i value of 2.1 nM.Comparison of both the ? 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 ? receptor binding of this pharmacophore.