Studies on the synthesis and opioid agonistic activities of mitragynine-related indole alkaloids: discovery of opioid agonists structurally different from other opioid ligands.
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 mu-, delta-, and kappa-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.
Takayama
Hiromitsu
H
Laboratory of Molecular Structure and Biological Function, Graduate School of Pharmaceutical Sciences, Chiba University, Yayoi-cho, 1-33, Inage-ku, Chiba 263-8522, Japan. htakayam@p.chiba-u.ac.jp
Ishikawa
Hayato
H
Kurihara
Mika
M
Kitajima
Mariko
M
Aimi
Norio
N
Ponglux
Dhavadee
D
Koyama
Fumi
F
Matsumoto
Kenjiro
K
Moriyama
Tomoyuki
T
Yamamoto
Leonard T
LT
Watanabe
Kazuo
K
Murayama
Toshihiko
T
Horie
Syunji
S
D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism; D004558:Electric Stimulation; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D026121:Indole Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D009020:Morphine / Q000737:chemistry / Q000494:pharmacology; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D011869:Radioligand Assay; D011957:Receptors, Opioid / Q000819:agonists*; D017465:Receptors, Opioid, delta / Q000819:agonists; D017473:Receptors, Opioid, kappa / Q000819:agonists; D017450:Receptors, Opioid, mu / Q000819:agonists; D046948:Secologanin Tryptamine Alkaloids / Q000737:chemistry*; D013329:Structure-Activity Relationship
D000700:Analgesics; D026121:Indole Alkaloids; D008024:Ligands; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D046948:Secologanin Tryptamine Alkaloids; D009020:Morphine; C001801:mitragynine