Synthesis of spiro-2,6-dioxopiperazine and spiro-2,6-dioxopyrazine scaffolds using amino acids in a three-component reaction to generate potential Sigma-1 (σ1) receptor selective ligands

Abstract

A library-friendly approach to generate new scaffolds is decisive for the development of molecular probes, drug like molecules and preclinical entities. Here, we present the design and synthesis of novel heterocycles with spiro-2,6-dioxopiperazine and spiro-2,6-pyrazine scaffolds through a three-component reaction using various amino acids, ketones, and isocyanides. Screening of select compounds over fifty CNS receptors including G-protein coupled receptors (GPCRs), ion channels, transporters, and enzymes through the NIMH psychoactive drug screening program indicated that a novel spiro-2,6-dioxopyrazine scaffold, UVM147, displays high binding affinity at sigma-1 (σ 1 ) receptor in the nanomolar range. In addition, molecular docking of UVM147 at the human σ 1 receptor have shown that it resides in the same binding site that was occupied by the ligand 4-IBP used to obtain a crystal structure of the human sigma −1 (σ 1 ) receptor.

Synthesis and Pharmacology of a Novel μ–δ Opioid Receptor Heteromer-Selective Agonist Based on the Carfentanyl Template

“…This reaction is a powerful tool to access a large variety of derivatives, making diversification library-friendly, , and involved in our case the use of acids (region A), amines (region B), isocyanides (region C), and 1-phenethylpiperidin-4-one (region D). The desired carfentanyl amides were all isolated in moderate to good yields, and Váradi et al approach was used in this work to synthesize the target compounds.…”

Small Molecules Selectively Targeting Sigma-1 Receptor for the Treatment of Neurological Diseases

“…The unsaturated spiro-2,6-dioxopyrazine 66 (UVM147) was identified as the most potent σ 1 selective ligand ( K i = 8 nM) from this approach, screening over 50 different CNS receptors including GPCRs, ion channels, transporters, and enzymes through the psychoactive drug screening program (PDSP) funded by the National Institute of Mental Health (NIMH). Importantly, 66 shows highly selective binding to σ 1 over σ 2 receptors ( K i σ 2 = 696 nM) and several crucial CNS targets including 5-HT 2B ( K i = 231 nM), 5-HT 7 ( K i = 2765 nM), α 2A ( K i = 3364 nM), D 4 ( K i = 1283 nM), DAT ( K i = 2562 nM), H 2 ( K i = 823 nM), and KOR ( K i = 1707 nM) . In addition, Lepovitz and Martin synthesized bioactive azaspirocycles via a novel, efficient diversity-oriented synthesis (DOS) strategy that featured a tandem sequence involving imine formation and an aza-Sakurai reaction to form the spirocyclic system, and subsequently intramolecular Pictet–Spengler cyclization with formaldehyde to build tetrahydroisoquinoline rings.…”

“…Compound 65 was identified with the best σ 1 binding affinity and subtype selectivity of the series (K i σ 1 = 5.9 nM; σ 2 = 563 nM). Later, a three component reaction of various amino acids, ketones, and isocyanides was reported by Majumdar and colleagues 173 to generate a library of various spiro-2,6-dioxopiperazines and spiro-2,6-pyrazine scaffolds with a piperidinyl group. The unsaturated spiro-2,6-dioxopyrazine 66 (UVM147) was identified as the most potent σ 1 selective ligand (K i = 8 nM) from this approach, screening over 50 different CNS receptors including GPCRs, ion channels, transporters, and enzymes through the psychoactive drug screening program (PDSP) funded by the National Institute of Mental Health (NIMH).…”

“…Importantly, 66 shows highly selective binding to σ 1 over σ 2 receptors (K i σ 2 = 696 nM) and several crucial CNS targets including 5-HT 2B (K i = 231 nM), 5-HT 7 (K i = 2765 nM), α 2A (K i = 3364 nM), D 4 (K i = 1283 nM), DAT (K i = 2562 nM), H 2 (K i = 823 nM), and KOR (K i = 1707 nM). 173 In addition, Lepovitz and Martin 174 synthesized bioactive azaspirocycles via a novel, efficient diversity-oriented synthesis (DOS) strategy that featured a tandem sequence involving imine formation and an aza-Sakurai reaction to form the spirocyclic system, and subsequently intramolecular Pictet−Spengler cyclization with formaldehyde to build tetrahydroisoquinoline rings. Azaspirocycle 67 shows a preference for the σ 1 receptor (K i = 8 nM) with moderate binding at σ 2 (K i = 152 nM) and α 2A (K i = 531 nM) receptor and weak affinity against a panel of approximately 44 other CNS proteins tested by the PDSP.…”