Potent and Selective Tetrahydroisoquinoline Kappa Opioid Receptor Antagonists of Lead Compound (3 R)- N-[1 R)-1-(Cyclohexylmethyl)-2-methylpropyl]-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (CDTic)

Journal of Medicinal Chemistry
Chad M KormosF Ivy Carroll

Abstract

Animal pharmacological studies suggest that potent and selective κ opioid receptor antagonists have potential as pharmacotherapies targeting depression, anxiety, and substance abuse (opiates, alcohol, nicotine, cocaine). We recently reported lead compound 1 as a new class of κ opioid receptor antagonists with only one basic amine group. Analogues were synthesized and evaluated for their in vitro opioid receptor antagonist properties using a [35S]GTPγS binding assay. All analogues were pure opioid receptor antagonists with no agonist activity. Compounds 1, 8, 9, 13, and 14 ( Ke values 0.058-0.64 nM) are highly potent and highly selective for the κ relative to the μ and δ opioid receptors. Favorable calculated physiochemical properties were confirmed in rat PK studies, demonstrating brain penetration for selected compounds 1, 9, and 13. High κ opioid receptor potency and selectivity and highly favorable calculated physiochemical and PK properties for brain penetration suggest these compounds should be considered for further development.

References

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Jul 26, 2017·ACS Medicinal Chemistry Letters·Chad M KormosF Ivy Carroll

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Citations

Jun 24, 2020·Peptides·Richard J Bodnar
Jun 28, 2019·Journal of the American Chemical Society·Jin-Fay TanNicolai Cramer

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