title: Benzoxazines. II. Synthesis, conformational analysis, and structure--activity relationships of 3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide derivatives as potent and long-acting serotonin-3 (5-HT3) receptor antagonists.
abstract: A series of 3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide derivatives was synthesized and evaluated for serotonin-3 (5HT3) receptor antagonistic activities by means of assays of 5-HT3 receptor binding and the ability to antagonize the von Bezold-Jarisch reflex in rats. Replacement of the 1,4-benzoxazine ring with a 1,4-benzthiepine ring or seven-membered ring (i.e., 1,5-benzoxepine or 1,5-benzthiepine) resulted in decreased affinity for 5-HT3 receptor. Introduction of substituents at the 2 position of the 1,4-benzoxazine ring increased the antagonistic activities (dimethyl > methyl > dihydro > phenyl). The compounds bearing a 9-methyl-9-azabicyclo[3.3.1]non-3-yl moiety as the basic part of 3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide derivatives were equipotent to those bearing 1-azabicyclo[2.2.2]oct-3-yl moiety. The 9-methyl-9-azabicyclo[3.3.1]non-3-yl moiety was confirmed to adopt a boat-chair conformation on the basis of both NMR studies and X-ray analysis. In this series, endo-6-chloro-3,4-dihydro-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2,2, 4-trimethyl-2H-1,4-benzoxazine-8-carboxamide showed the highest affinity for 5-HT3 receptors (Ki = 0.019 nM), and a long-lasting 5-HT3 receptor antagonistic activity as evidenced by antagonism to the von Bezold--Jarisch reflex in rats. Such a long-lasting 5-HT3 receptor antagonism would be attributed to the introduction of both two methyl groups at the 2 position of the benzoxazine ring and the 9-methyl-9-azabicyclo[3.3.1]non-3-yl moiety, which adopts the boat-chair conformation.
authors.affiliation: Research Laboratory, Yoshitomi Pharmaceutical Industries Ltd., Fukuoka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kuroita
authors.forename: N
authors.initials: N
authors.lastname: Marubayashi
authors.forename: M
authors.initials: M
authors.lastname: Sano
authors.forename: K
authors.initials: K
authors.lastname: Kanzaki
authors.forename: K
authors.initials: K
authors.lastname: Inaba
authors.forename: T
authors.initials: T
authors.lastname: Kawakita
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D017829:Granisetron / Q000493:pharmacokinetics; D006439:Hemodynamics / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008968:Molecular Conformation; D010078:Oxazines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000737:chemistry / Q000187:drug effects; D012018:Reflex / Q000187:drug effects / Q000502:physiology; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D017829:Granisetron; D010078:Oxazines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists