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Conformational analysis, pharmacophore identification, and comparative molecular field analysis of ligands for the neuromodulatory sigma 3 receptor.

Publication ,  Journal Article
Myers, AM; Charifson, PS; Owens, CE; Kula, NS; McPhail, AT; Baldessarini, RJ; Booth, RG; Wyrick, SD
Published in: Journal of medicinal chemistry
November 1994

Molecular modeling studies were carried out on a series of 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes (phenylaminotetralins, PATs), several PAT structural analogs, and various non-PAT ligands that demonstrate a range of affinities for a novel sigma 3 receptor linked to stimulation of tyrosine hydroxylase and dopamine synthesis in rodent brain. In an effort to develop a ligand-binding model for the sigma 3 receptor, a pharmacophore mapping program (DISCO) was used to identify structural features that are common to ligands that exhibit moderate to high binding affinity for sigma 3 sites. DISCO then was utilized to propose a common pharmacophoric region that included one low-energy conformation of each compound in the training set. The resulting alignment was utilized in a comparative molecular field analysis (CoMFA) study in an attempt to correlate the steric and electrostatic fields of the molecules with the respective binding affinities at the sigma 3 receptor. A suitably predictive model was obtained from the CoMFA analysis which will be employed in the development of additional PAT analogs that could potentially display high affinity and selectivity for the sigma 3 receptor. The excluded volumes which resulted from comparing molecular volumes of active and inactive compounds were visualized to examine the limits of steric tolerance imposed by the sigma 3 receptor.

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Published In

Journal of medicinal chemistry

DOI

EISSN

1520-4804

ISSN

0022-2623

Publication Date

November 1994

Volume

37

Issue

24

Start / End Page

4109 / 4117

Related Subject Headings

  • Tetrahydronaphthalenes
  • Structure-Activity Relationship
  • Rodentia
  • Receptors, sigma
  • Molecular Conformation
  • Models, Molecular
  • Medicinal & Biomolecular Chemistry
  • Ligands
  • Animals
  • 1115 Pharmacology and Pharmaceutical Sciences
 

Citation

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Myers, A. M., Charifson, P. S., Owens, C. E., Kula, N. S., McPhail, A. T., Baldessarini, R. J., … Wyrick, S. D. (1994). Conformational analysis, pharmacophore identification, and comparative molecular field analysis of ligands for the neuromodulatory sigma 3 receptor. Journal of Medicinal Chemistry, 37(24), 4109–4117. https://doi.org/10.1021/jm00050a008
Myers, A. M., P. S. Charifson, C. E. Owens, N. S. Kula, A. T. McPhail, R. J. Baldessarini, R. G. Booth, and S. D. Wyrick. “Conformational analysis, pharmacophore identification, and comparative molecular field analysis of ligands for the neuromodulatory sigma 3 receptor.Journal of Medicinal Chemistry 37, no. 24 (November 1994): 4109–17. https://doi.org/10.1021/jm00050a008.
Myers AM, Charifson PS, Owens CE, Kula NS, McPhail AT, Baldessarini RJ, et al. Conformational analysis, pharmacophore identification, and comparative molecular field analysis of ligands for the neuromodulatory sigma 3 receptor. Journal of medicinal chemistry. 1994 Nov;37(24):4109–17.
Myers, A. M., et al. “Conformational analysis, pharmacophore identification, and comparative molecular field analysis of ligands for the neuromodulatory sigma 3 receptor.Journal of Medicinal Chemistry, vol. 37, no. 24, Nov. 1994, pp. 4109–17. Epmc, doi:10.1021/jm00050a008.
Myers AM, Charifson PS, Owens CE, Kula NS, McPhail AT, Baldessarini RJ, Booth RG, Wyrick SD. Conformational analysis, pharmacophore identification, and comparative molecular field analysis of ligands for the neuromodulatory sigma 3 receptor. Journal of medicinal chemistry. 1994 Nov;37(24):4109–4117.
Journal cover image

Published In

Journal of medicinal chemistry

DOI

EISSN

1520-4804

ISSN

0022-2623

Publication Date

November 1994

Volume

37

Issue

24

Start / End Page

4109 / 4117

Related Subject Headings

  • Tetrahydronaphthalenes
  • Structure-Activity Relationship
  • Rodentia
  • Receptors, sigma
  • Molecular Conformation
  • Models, Molecular
  • Medicinal & Biomolecular Chemistry
  • Ligands
  • Animals
  • 1115 Pharmacology and Pharmaceutical Sciences