Synthesis of N-Alkyl-octahydroisoquinolin-1-one-8-carboxamide Libraries Using a Tandem Diels–Alder/Acylation Sequence

Abstract

A synthetic sequence was developed in which a diene containing an attached secondary amine was reacted with maleic anhydride to afford the title structures in one step. The reaction involves a Diels-Alder reaction combined with a transacylation reaction of the imide group. A series of six scaffolds was constructed using this methodology. Each scaffold was subsequently reacted with 12 amines to afford a library containing 72 compounds.

Seeking (and Finding) Biased Ligands of the Kappa Opioid Receptor

“…11 In our KOR program, we had identified appropriate chemical matter during the course of two separate projects. In one, an exploratory library of 72 isoquinolinones prepared as a part of the KU Chemical Methodology and Library Development program 12 was screened in the UNC Psychoactive Drug Screening Program directed by Bryan Roth, which uses radioligand displacement assays to identify receptor binders. Remarkably, this screen directly afforded a highly potent and selective KOR agonist (K i = 5 nM for KOR, 3550 nM for MOR, and >10 μM for DOR; see Figure 2 for an isoquinolinone hit).…”

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).…”

Comprehensive overview of biased pharmacology at the opioid receptors: biased ligands and bias factors

“…The isoquinolinone lead compound (Figure 7) was found to be highly selective for KOR over both MOR and DOR. [230][231] Later, this isoquinolinone lead compound was optimized by substituting the chlorine on the aromatic ring and the benzyl-group on the nitrogen of the isoquinolinone moiety by a methyl and 2-fluorobenzyl respectively, affording 2.1, and by a bromide and phenyl, giving 2.2 (Figure 7). The bias factors of these analogs were calculated using the operational model (Equation 2) with U69,593 as a comparison, resulting in factors of 1.…”