Prev. Article Next Article Table of Contents

Article

Synthesis and Preliminary In vitro Investigation of Bivalent Ligands Containing Homo- and Heterodimeric Pharmacophores at μ, δ, and κ Opioid Receptors

Supporting Info

Xuemei Peng,^† Brian I. Knapp,^‡ Jean M. Bidlack,^‡ and John L. Neumeyer*^†

Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, Massachusetts 02478, and Department of Pharmacology and Physiology, School of Medicine and Dentistry, University of Rochester, Rochester, New York 14642

J. Med. Chem., 2006, 49 (1), pp 256–262

DOI: 10.1021/jm050577x

Publication Date (Web): December 3, 2005

†

Harvard Medical School.

‡

University of Rochester.

To whom correspondence should be addressed. Phone: 617-855-3388. Fax: 617-855-2519. E-mail: Neumeyer@mclean.harvard.edu.

Abstract

A series of homo- and heterodimeric ligands containing κ agonist and μ agonist/antagonist pharmacophores joined by a linker chain of varying lengths was synthesized and evaluated in vitro by their binding affinity at μ, δ, and κ opioid receptors. The functional activities of these compounds were measured in the [³⁵S]GTPγS binding assay. The data suggest that the stereochemistry of the pharmacophores, the N-substituents of the pharmacophore, ester linkages, and the spacer length were crucial factors for optimum interactions of such ligands at opioid receptor binding sites. These novel ligands as well as their pharmacological properties will serve as the basis for our continuing investigation of such bivalent ligands as probes of the opioid receptor oligomerization phenomena and for in vivo studies as analgesics.

View: Full Text HTML | Hi-Res PDF