Received for publication April 11, 2006.
Revised July 19, 2006.
Accepted for publication July 20, 2006.

Tethered Yohimbine Analogs as Selective Human _2C-Adrenergic Receptor Ligands

Abstract

Yohimbine is a potent and relatively nonselective ₂-AR antagonist. In an earlier report, we have demonstrated that dimeric yohimbine analogs containing methylene and methylene-diglycine tethers were highly selective human _2C-AR ligands. Little work has examined the role of the tether group or the absence of the second yohimbine pharmacophore on selectivity for the human ₂-AR subtypes. The goal of our study was to determine the binding affinities and functional subtype-selectivities of a series of tethered yohimbine ligands, in the absence of the second pharmacophore. The profiles of pharmacological activity for the yohimbine analogs were examined on the three human ₂-AR subtypes expressed in Chinese hamster ovary (CHO) cells using receptor binding and cAMP inhibition assays. All of the tethered yohimbine analogs exhibited higher binding affinities at the _2C- vs. _2A- and _2B-AR subtypes. Notably, the benzyl carboxy alkyl amine and the carboxy alkyl amine analogs exhibited a 43- and 1995-fold and 295- and 54-fold selectivity in binding to the _2C- vs. _2A- and _2B-ARs, respectively. Data from luciferase reporter gene assays confirmed the functional antagonist activities and selectivity profiles of selected compounds from the tethered series. The data demonstrate that the second pharmacophore may not be essential to obtain _2C-AR subtype-selectivity, previously observed with the dimers. Further changes in the nature of the tether will help in optimization of the structure activity relationship to obtain potent and selective _2C-AR ligands. These compounds may be used as pharmacological probes and in the treatment of human disorders.

Key words: adrenoceptor, alpha, binding, functional, ligand, selective