Pharmacological characterization of FK1052, a dihydropyridoindole derivative, as a new serotonin 3 and 4 dual receptor antagonist.
(+)-8,9-Dihydro-10-dihydro-10-methyl-7-[(5-methyl-4-imidazolyl) methyl]pyrido-[1,2-a]indol-6(7H)-one hydrochloride (FK1052) is a newly designed and synthesized 5-hydroxytryptamine (5-HT)3 receptor antagonist with 5-HT4 receptor antagonistic activity. This compound, as well as ondansetron and granisetron, dose-dependently inhibited the von Bezold-Jarish reflex, a 5-HT3 receptor-mediated response, after intravenous (i.v.) and intraduodenal (i.d.) dosing to rats. The ID50 values showed FK1052 (0.28 microgram/kg, i.v., 5.23 micrograms/kg, i.d.) to be more potent than ondansetron (5.23 micrograms/kg, i.v., 170 micrograms/kg, i.d.) and granisetron (0.70 micrograms/kg, i.v., 66 micrograms/kg, i.d.). Furthermore, bioavailabilities of the test drugs by ID50 ratio (i.d./i.v.) showed that FK1052(17) was better absorbed than ondansetron(33) and granisetron(94) and possessed a similar duration of action to that of ondansetron and granisetron. We also examined the effects on 2-methyl-5-HT-, 5-HT- and 5-methoxytryptamine-induced contractions of guinea pig isolated ileum. FK1052, ondansetron and granisetron concentration-dependently inhibited 2-methyl-5-HT, a 5-HT3 agonist-induced contraction. The pA2 values for the 5-HT3 receptor indicated that FK1052 (8.36) was 40 times and three times more potent than ondansetron (6.79) and granisetron (7.86), respectively. FK1052, unlike ondansetron and granisetron, inhibited the 5-HT4-mediated component of concentration-response curve to 5-HT. Furthermore, FK1052 suppressed 5-methoxytryptamine, a 5-HT4 agonist-induced contraction in a concentration-dependent but insurmountable manner.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Pharmacology, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
Y
Y
Nagakura
M
M
Kadowaki
K
K
Tokoro
M
M
Tomoi
J
J
Mori
M
M
Kohsaka
D008735:5-Methoxytryptamine / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001919:Bradycardia / Q000139:chemically induced; D004558:Electric Stimulation; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D012701:Serotonin / Q000031:analogs & derivatives / Q000494:pharmacology; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
D007093:Imidazoles; D007211:Indoles; D017448:Receptors, Dopamine D2; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C081308:FK 1052; D012701:Serotonin; D008735:5-Methoxytryptamine; C045918:2-methyl-5-HT; D006632:Histamine; D000109:Acetylcholine