ABSTRACT
BACKGROUND: New treatments for stress-related disorders including depression, anxiety, and substance use disorder are greatly needed. Kappa opioid receptors are expressed in the central nervous system, including areas implicated in analgesia and affective state. Although kappa opioid receptor agonists share the antinociceptive effects of mu opioid receptor agonists, they also tend to produce negative affective states. In contrast, selective kappa opioid receptor antagonists have antidepressant- and anxiolytic-like effects, stimulating interest in their therapeutic potential. The prototypical kappa opioid receptor antagonists (e.g., norBNI, JDTic) have an exceptionally long duration of action that complicates their use in humans, particularly in tests to establish safety. This study was designed to test dose- and time-course effects of novel kappa opioid receptor antagonists with the goal of identifying short-acting lead compounds for future medication development. METHODS: We screened 2 novel, highly selective kappa opioid receptor antagonists (CYM-52220 and CYM-52288) with oral efficacy in the warm water tail flick assay in rats to determine initial dose and time course effects. For comparison, we tested existing kappa opioid receptor antagonists JDTic and LY-2456302 (also known as CERC-501 or JNJ-67953964). RESULTS: In the tail flick assay, the rank order of duration of action for the antagonists was LY-2456302 < CYM-52288 < CYM-52220 << JDTic. Furthermore, LY-2456302 blocked the depressive (anhedonia-producing) effects of the kappa opioid receptor agonist U50,488 in the intracranial self-stimulation paradigm, albeit at a higher dose than that needed for analgesic blockade in the tail flick assay. CONCLUSIONS: These results suggest that structurally diverse kappa opioid receptor antagonists can have short-acting effects and that LY-2456302 reduces anhedonia as measured in the intracranial self-stimulation test.
Subject(s)
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer/pharmacology , Analgesics, Non-Narcotic/pharmacology , Anti-Anxiety Agents/pharmacology , Antidepressive Agents/pharmacology , Behavior, Animal/drug effects , Benzamides/pharmacology , Narcotic Antagonists/pharmacology , Piperidines/pharmacology , Pyrrolidines/pharmacology , Receptors, Opioid, kappa/antagonists & inhibitors , Tetrahydroisoquinolines/pharmacology , 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer/administration & dosage , Analgesics, Non-Narcotic/administration & dosage , Animals , Anti-Anxiety Agents/administration & dosage , Antidepressive Agents/administration & dosage , Benzamides/administration & dosage , Drug Development , Drug Evaluation, Preclinical , Male , Narcotic Antagonists/administration & dosage , Piperidines/administration & dosage , Pyrrolidines/administration & dosage , Rats , Rats, Sprague-Dawley , Receptors, Opioid, kappa/agonists , Tetrahydroisoquinolines/administration & dosageABSTRACT
The design and discovery of JDTic as a potent and selective kappa opioid receptor antagonist used the N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine pharmacophore as the lead structure. In order to determine if the 3-methyl or 4-methyl groups were necessary in JDTic and JDTic analogs for antagonistic activity, compounds 4a-c, and 4d-f which have either the 3-methyl or both the 3- and 4-methyl groups removed, respectively, from JDTic and analogs were synthesized and evaluated for their in vitro opioid receptor antagonist activities using a [(35)S]GTPγS binding assay. Other ADME properties were also assessed for selected compounds. These studies demonstrated that neither the 3-methyl or 3,4-dimethyl groups present in JDTic and analogs are required to produce potent and selective κ opioid receptor antagonists.
Subject(s)
Drug Design , Narcotic Antagonists/chemical synthesis , Piperidines/chemistry , Receptors, Opioid, kappa/antagonists & inhibitors , Tetrahydroisoquinolines/chemistry , Animals , Cell Membrane Permeability/drug effects , Dogs , Drug Evaluation, Preclinical , Half-Life , Madin Darby Canine Kidney Cells , Narcotic Antagonists/metabolism , Narcotic Antagonists/pharmacokinetics , Piperidines/metabolism , Piperidines/pharmacokinetics , Protein Binding , Receptors, Opioid, kappa/metabolism , Tetrahydroisoquinolines/metabolism , Tetrahydroisoquinolines/pharmacokineticsABSTRACT
N-Substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines are a class of pure opioid receptor antagonists with a novel pharmacophore. This opioid receptor antagonist pharmacophore was used as a lead structure to design and develop several interesting and useful opioid receptor antagonists. In this review we describe: 1)â early SAR studies that led to the discovery of LY255582 and analogues that are nonselective opioid receptor antagonists developed for the treatment of obesity; 2)â the discovery and commercialization of LY246736 (alvimopan; ENTEREG®), a peripherally selective opioid receptor antagonist that accelerates the time to upper and lower GI recovery following surgeries that include partial bowel resection with primary anastomosis; and 3)â the discovery and development of the potent and selective κ opioid receptor antagonist JDTic and analogues as potential pharmacotherapies for treating depression, anxiety, and substance abuse (nicotine, alcohol, and cocaine). In addition, the use of JDTic for obtaining the X-ray structure of the human κ opioid receptor is discussed.