Synthesis and biological evaluation of conformationally restricted 2-(1-pyrrolidinyl)-N-[2-(3,4-dichlorophenyl)ethyl]-N-methylethylenediamines as .sigma. receptor ligands. 1. Pyrrolidine, piperidine, homopiperidine, and tetrahydroisoquinoline classes
The synthesis and sigma 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 NN-dialkyl), ethylenediamine, N-alkyl, and phenylethyl portions of this sigma receptor...
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Published in | Journal of medicinal chemistry Vol. 35; no. 23; pp. 4334 - 4343 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
WASHINGTON
American Chemical Society
01.11.1992
Amer Chemical Soc |
Subjects | |
Online Access | Get full text |
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Summary: | The synthesis and sigma 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 NN-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 [H-3](+)-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-(l-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 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 a receptor binding of this pharmacophore. |
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Bibliography: | istex:A611CC805F8B7A543F9D5F3C3BBC5C4BC794A913 ark:/67375/TPS-3XJQSMKW-3 |
ISSN: | 0022-2623 1520-4804 |
DOI: | 10.1021/jm00101a011 |