Characterization of Opioid and ORL1 Receptors

Abstract

This unit describes methods for studying activity at opioid receptor subtypes and the ORL1 receptor using conventional radioligand binding assay methods as well as procedures for quantitating functional activity of these receptors by measuring agonist‐induced G protein activation with [35S]GTPγS binding in a manner analogous to traditional receptor‐binding methods. These procedures permit the assessment of the agonist or antagonist character of compounds in a rapid manner that, like most radioligand binding methodologies, is also amenable to high throughput technologies.

N-Alkylation-Intramolecular Michael Addition: New Reaction Manifold for High Throughput Annulation of Amines

“…As a demonstration of the utility of the new SPAn reagents to generate structure-activity relationship (SAR) information, 6b-naltrexamine a7 was derivatized with reagents 7/8 and 15/16 (Table 2). The novel heterocyclic derivatives 1m,n and 2r,s (obtained as mixture of their respective diastereomers) were screened for binding (K i ) against the human opioid receptors m, k, and d. 6 The resulting nascent SAR indicates that agents 1m and 2r are potent dual k/d ligands with ca. 6-to 13-fold selectivity over m. Interestingly, the m receptor appears relatively insensitive to the change in the pendent ester versus carboxylic acid group (esters 1m/2r versus acids 1n/2s).…”