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).

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 ( K_e 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,

SUBMITTER: Kormos CM 

PROVIDER: S-EPMC6692071 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature