Detailed In Vitro Pharmacological Characterization of the Clinically Viable Nociceptin/Orphanin FQ Peptide Receptor Antagonist BTRX-246040

Abstract

The peptide nociceptin/orphanin FQ (N/OFQ) is the natural ligand of the N/OFQ receptor (NOP) which is widely expressed in the central and peripheral nervous system. Selective NOP antagonists are worthy of testing as innovative drugs to treat depression, Parkinson's disease, and drug abuse. The aim of this study was to perform a detailed in vitro characterization of BTRX-246040 (also known as LY2940094, [2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methylpyrazol-1-yl]-3-pyridyl]methanol)a novel NOP antagonist that has been already studied in humans. BTRX-246040 has been tested in vitro in the following assays: calcium mobilization in cells expressing NOP and classical opioid receptors and chimeric G proteins, BRET assay measuring NOP interaction with G proteins and -arrestins, the label free dynamic mass redistribution assay, and the electrically stimulated mouse vas deferens. BTRX-246040 was systematically compared to the standard NOP antagonist SB-612111. In all assays BTRX-246040 behaves as a pure and selective antagonist at human recombinant and murine native NOP receptors displaying 3-10 fold higher potency than the standard antagonist SB-612111. BTRX-246040 is as an essential pharmacological tool to further investigate the therapeutic potential of NOP antagonists in preclinical and clinical studies. Significance Statement NOP antagonists may be innovative antidepressant drugs. In this research the novel clinically viable NOP antagonist BTRX-246040 has been deeply characterized in vitro in a panel of assays. BTRX-246040 resulted a pure, potent and selective NOP antagonist.

The NOP antagonist BTRX-246040 increases stress resilience in mice without affecting adult neurogenesis in the hippocampus

“…BTRX-246040 is a selective and potent NOP antagonist (Ferrari et al, 2020;Statnick et al, 2016) under development for the treatment of depression, eating disorders and alcohol abuse (Browne and Lucki, 2019;Witkin et al, 2019). In a small clinical proof of concept study performed in patients with major depressive disorders (MDD) BTRX-246040 (40 mg, p.o.)…”

“…The in vitro pharmacological activity of BTRX-246040 has been recently characterized in detail and compared to those of the standard NOP antagonist SB-612111. BTRX-246040 is a pure and selective antagonist at human recombinant and murine native NOP receptors displaying 3 -10 fold higher potency than the standard antagonist SB-612111 (Ferrari et al, 2020).…”

Biased Agonism at Nociceptin/Orphanin FQ Receptors: A Structure Activity Study on N/OFQ(1–13)-NH2

“…Similar results were obtained using compound 40 and 43 as NOP agonists; the p A 2 values of SB-612111 calculated from these experiments were 7.95 (CL 95% 7.43–8.47) and 7.77 (CL 95% 7.32–8.21), respectively (see Figure S1 of the Supporting Information). Thus, SB-612111 competitively antagonized the effects of N/OFQ, , N/OFQ(1–13)-NH 2 , and compounds 40 and 43 , showing similar p A 2 values. This demonstrated that similar to N/OFQ and N/OFQ(1–13)-NH 2 , compounds 40 and 43 activate the NOP receptor by interacting with the orthosteric binding pocket that has been described at the atomic level in previous NOP/C-24 and NOP/SB-612111 crystal structure studies.…”

The role of nociceptin in opioid regulation of brain functions

“…При этом не было отмечено положительного эффекта препарата на такие показатели нарушения сна как ранняя бессонница (трудности при засыпании), средняя (многократные пробуждения в течение ночи) и поздняя бессонница (ранние пробуждения) [79]. В настоящее время свойства LY2940094 (BTRX-246040) активно изучают в экспериментах in vivo и in vitro [81].…”