Synthesis and pharmacological characterization of novel 6-fluorochroman derivatives as potential 5-HT1A receptor antagonists.
A series of novel 6-fluorochroman derivatives was prepared and evaluated as antagonists for the 5-HT1A receptor. N-2-[[(6-Fluorochroman-8-yl)oxy]ethyl]-4-(4-methoxyphenyl)butylami ne (3; J. Med. Chem. 1997, 40, 1252-1257) was chosen as a lead, and structural modifications were done on the aliphatic portion of the chroman ring, the tether linking the middle amine and the terminal aromatic ring, the aromatic ring, and lastly the amine. Radioligand binding assays proved that the majority of the novel compounds behaved as good to excellent ligands at the 5-HT1A receptor, some of which were selective with respect to alpha1-adrenergic and D2-dopaminergic receptors. The antagonist activity of the compounds was assessed in the forskolin-stimulated adenylate cyclase assays in CHO cells expressing the human 5-HT1A receptors. Among the modifications attempted, introduction of an oxo or an optically active hydroxy moiety at the chroman C-4 position was effective in ameliorating the receptor selectivity. Six analogues were selected through the in vitro screens and further evaluated for their in vivo activities. A 4-oxochroman derivative (31n), having a terminal 1, 3-benzodioxole ring, demonstrated antagonist activities toward 8-OH-DPAT-induced behavioral and electrophysiological responses in rats.
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Company, Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
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T
Yasunaga
T
T
Kimura
R
R
Naito
T
T
Kontani
F
F
Wanibuchi
H
H
Yamashita
T
T
Nomura
S
S
Tsukamoto
T
T
Yamaguchi
T
T
Mase
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D016466:CHO Cells; D002867:Chromones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D006224:Cricetinae; D004149:Dioxoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004594:Electrophysiology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D011903:Raphe Nuclei / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000096:biosynthesis / Q000187:drug effects*; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C113345:8-(2-(4-(1,3-benzodioxol-5-yl)butylamino)ethoxy)-6-fluorochroman-4-one; D002867:Chromones; D004149:Dioxoles; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D005576:Colforsin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000262:Adenylyl Cyclases