Binding of Substituted and Conformationally Restricted Derivatives of N-(3-phenyl-n-propyl)-1-phenyl-2-aminopropane at Sigma-Receptors

J Med Chem. 1991 Jun;34(6):1855-9. doi: 10.1021/jm00110a015.

Abstract

Certain benzomorphans, such as N-allylnormetazocine, are classical "sigma-opiates" that bind both at sigma and phencyclidine (PCP) binding sites with modest affinity. Recently, we identified N-substituted 2-phenylaminoethane as being the primary sigma-pharmacophore of the benzomorphans and demonstrated that 1-phenyl-2-aminopropane (2) derivatives, depending upon their terminal amine substituents, constitute a novel class of high-affinity sigma-selective agents. With this pharmacophore, it is shown in the present investigation that the aromatic hydroxyl group (a prime feature of all the sigma-opiates) contributes little to the binding of 2 at sigma-sites. It is also demonstrated that an N-substituted aminotetralin moiety (such as 17, a conformationally restricted analogue of 2) may also be considered a sigma-opiate pharmacophore. Unlike the sigma-opiates, derivatives of 2 and 17 display no affinity for PCP sites and must consequently lack those structural features important for the binding of benzomorphans at PCP sites. Because 3-phenylpiperidines and related sigma-ligands also possess a phenylalkylamine imbedded within their structures, we propose that the 2-phenylaminoethane moiety is a common sigma-pharmacophore for derivatives of 2, the 3-phenylpiperidines, and the sigma-opiates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism
  • Guinea Pigs
  • Microsomes / metabolism
  • Phencyclidine / metabolism
  • Propylamines / metabolism*
  • Radioligand Assay
  • Receptors, Opioid / metabolism*
  • Receptors, sigma
  • Substrate Specificity

Substances

  • Propylamines
  • Receptors, Opioid
  • Receptors, sigma
  • N-(3-phenyl-n-propyl)-1-phenyl-2-aminopropane
  • Phencyclidine