Studies on the Synthesis and Opioid Agonistic Activities of Mitragynine-Related Indole Alkaloids:  Discovery of Opioid Agonists Structurally Different from Other Opioid Ligands

• Published in: Journal of medicinal chemistry Vol. 45; no. 9; pp. 1949 - 1956
• Main Authors: Takayama, Hiromitsu, Ishikawa, Hayato, Kurihara, Mika, Kitajima, Mariko, Aimi, Norio, Ponglux, Dhavadee, Koyama, Fumi, Matsumoto, Kenjiro, Moriyama, Tomoyuki, Yamamoto, Leonard T, Watanabe, Kazuo, Murayama, Toshihiko, Horie, Syunji
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 25-04-2002
• Subjects: Analgesics; Analgesics - chemical synthesis; Analgesics - chemistry; Analgesics - pharmacology; Animals; Biological and medical sciences; Brain - metabolism; Electric Stimulation; Guinea Pigs; Ileum - drug effects; Ileum - physiology; In Vitro Techniques; Indole Alkaloids - chemical synthesis; Indole Alkaloids - chemistry; Indole Alkaloids - pharmacology; Ligands; Medical sciences; Mice; Models, Molecular; Morphine - chemistry; Morphine - pharmacology; Muscle Contraction; Muscle, Smooth - drug effects; Muscle, Smooth - physiology; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Radioligand Assay; Receptors, Opioid - agonists; Receptors, Opioid, delta - agonists; Receptors, Opioid, kappa - agonists; Receptors, Opioid, mu - agonists; Secologanin Tryptamine Alkaloids - chemistry; Structure-Activity Relationship; Agonist; Angular nitrogen heterocycle; Opioid receptor; Central nervous system; Modeling; Ester; Alkaloid; Guinea pig; Structure activity relation; Tertiary alcohol; Vinylic compound; Molecular model; Aromatic compound; Enol ether; Semiempirical method; Chemical synthesis; Ether; Rodentia; Gut; Tetracyclic compound; Muscle contraction; Ileum; Spiran; In vivo; Vertebrata; Mammalia; Analgesic; Mouse; Animal; Affinity; AM1 method; Brain (vertebrata)
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm010576e

Mitragynine (1) is a major alkaloidal component in the Thai traditional medicinal herb, Mitragyna speciosa, and has been proven to exhibit analgesic activity mediated by opioid receptors. By utilizing this natural product as a lead compound, synthesis of some derivatives, evaluations of the structure−activity relationship, and surveys of the intrinsic activities and potencies on opioid receptors were performed with guinea pig ileum. The affinities of some compounds for μ-, δ-, and κ-receptors were determined in a receptor binding assay. The essential structural moieties in the Corynanthe type indole alkaloids for inducing the opioid agonistic activity were also clarified. The oxidative derivatives of mitragynine, i.e., mitragynine pseudoindoxyl (2) and 7-hydroxymitragynine (12), were found as opioid agonists with higher potency than morphine in the experiment with guinea pig ileum. In addition, 2 induced an analgesic activity in the tail flick test in mice.