title: Delta Opioid Receptor (DOR) Ligands and Pharmacology: Development of Indolo- and Quinolinomorphinan Derivatives Based on the Message-Address Concept.
abstract: The pharmacology of the delta opioid receptor (DOR) has lagged, mainly due to the lack of an agonist with high potency and selectivity in vivo. The DOR is now receiving increasing attention, and there has been progress in the synthesis of better novel ligands. The discovery of a selective receptor DOR antagonist, naltrindole (NTI), stimulated the design and synthesis of (±)TAN-67, which was designed based on the message-address concept and the accessory site theory. Intensive studies using (±)TAN-67 determined the DOR-mediated various pharmacological effects, such as antinociceptive effects for painful diabetic neuropathy and cardiovascular protective effects. We improved the agonist activity of TAN-67 to afford SN-28, which was modified to KNT-127, a novel compound that improved the blood-brain barrier permeability. In addition, KNT-127 showed higher selectivity for the DOR and had potent agonist activity following systemic administration. Interestingly, KNT-127 produced no convulsive effects, unlike prototype DOR agonists. The KNT-127 type derivatives with a quinolinomorphinan structure are expected to be promising candidates for the development of therapeutic DOR agonists.
authors: Department of Neuropsychopharmacology, National Center of Neurology and Psychiatry, National Institute of Mental Health, Tokyo, 187-8553, Japan.
authors: Akiyoshi
authors: A
authors: Saitoh
authors: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki, 305-8575, Japan. nagase.hiroshi.gt@u.tsukuba.ac.jp.
authors: Hiroshi
authors: H
authors: Nagase
mesh_terms: D000701:Analgesics, Opioid / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology*; D008024:Ligands; D009019:Morphinans / Q000138:chemical synthesis / Q000494:pharmacology*; D015363:Quinolones / Q000138:chemical synthesis / Q000494:pharmacology*; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000701:Analgesics, Opioid; D007211:Indoles; D008024:Ligands; D009019:Morphinans; D015363:Quinolones; D017465:Receptors, Opioid, delta
keywords: (−)TAN-67; Analgesic; Antidepressant; Antitussive; Anxiolytic; TRK-850; δ Opioid receptor