N-Alkyl-octahydroisoquinolin-1-one-8-carboxamides: Selective and Nonbasic κ-Opioid Receptor Ligands

Abstract

Herein we report that N-alkyl-octahydroisoquinolin-1-one-8-carboxamides are a novel class of readily-synthesized, selective ϰ-opioid receptor (KOR) ligands. A striking feature of this class of compounds is the absence of any basic nitrogen atoms. Many of these compounds have demonstrated exclusive affinity for the KOR over not only the δ-opioid receptor (DOR) and the μ-opioid receptor (MOR), but 38 other GPCR targets as well. The general binding affinity of this class of compounds for the KOR combined with a streamlined route for analog synthesis provide strong motivation for pursuing this interesting new scaffold as a basis toward new probes targeting the KOR.

Chemotype-selective Modes of Action of κ-Opioid Receptor Agonists

“…The compounds tested in these assays represent four chemically distinct groups of KORselective agonists of widely differing structural types and classes ( Fig. 1): the peptide dynorphin A(1-17), the arylacetamide U-69593, and the non-charged ligands salvinorin A (24) and the octahydroisoquinolinone carboxamide 1xx (25). We first describe the effects that the different mutations have on the affinities and potencies of the tested ligands and then describe structural models of the bound ligands and propose structural explanations for some of these effects.…”

“…Mode for 1xx-Some members of the recently discovered octahydroisoquinolinone class are specific KOR agonists with affinities in the low to mid nanomolar range (5-200 nM) and are non-basic (25); one of the best binding members (1xx) was chosen for study in the current work. The putative binding mode was identified for 1xx from the best scoring docked solution; the results for 1xx are presented in Fig.…”

“…It is generally thought that these basic residues interact specifically with acidic residues unique to the KOR in the address region of the receptor (22,23). The other ligands are small molecules: U-69593, an oxaspiro member of the arylacetamide class; salvinorin A, a highly potent and selective, non-nitrogenous hallucinogenic neoclerodane diterpenoid (24); and compound 1xx, a recently discovered non-basic full agonist octahydroisoquinolinone carboxamide with nanomolar potency as well as 700-and 2000-fold selectivity for KOR over MOR and DOR, respectively (25). Models of the different ligands bound to the KOR crystal structure were generated by minimally biased docking and assessed in the context of our biochemical studies.…”

Development of Functionally Selective, Small Molecule Agonists at Kappa Opioid Receptors

“…In this work, which was done in collaboration with colleagues at Sanford-Burnham Research Institute and Duke University, the National Institutes of Health Small Molecule Repository was screened to identify KOR ligands based on activation of ␤arrestin2 recruitment (35,36). The isoquinolinone scaffold arose from a 72-member library prepared by a tandem DielsAlder acylation reaction that was screened for binding at potential GPCR targets by the NIMH Psychoactive Drug Screening Program (37,38). The lead isoquinolinone was reported as a KOR agonist showing selectivity and high binding affinity for KOR over MOR, DOR, and other screened GPCRs (37,38); moreover, the triazole lead also displayed high selectivity for KOR over MOR and DOR ( Fig.…”

“…The isoquinolinone scaffold arose from a 72-member library prepared by a tandem DielsAlder acylation reaction that was screened for binding at potential GPCR targets by the NIMH Psychoactive Drug Screening Program (37,38). The lead isoquinolinone was reported as a KOR agonist showing selectivity and high binding affinity for KOR over MOR, DOR, and other screened GPCRs (37,38); moreover, the triazole lead also displayed high selectivity for KOR over MOR and DOR ( Fig. 1) (35,36).…”