3,4-Dihydro-3-amino-2H-1-benzopyran derivatives as 5-HT1A receptor ligands and potential anxiolytic agents. 1. Synthesis and structure--activity relationship studies.
A series of 3,4-dihydro-3-amino-2H-1-benzopyran derivatives were prepared in order to determine the necessary structural requirements for good affinity for 5-HT1A receptors and high selectivity versus other receptors. Modifications of the extracyclic amino substituents, the length of the alkyl side chains, and their substituents were explored. The best compounds (9g, 9k, 15b, 15d) possess imido or sulfonamido functional groups with a preferential length of four methylenes for the side chain. After resolution, the dextrorotatory enantiomers showed better affinity and selectivity for 5-HT1A receptors. These compounds have been proven to be full agonists. 9g and its enantiomers showed anxiolytic activity in vivo in various comportemental models. The compound (+)-9g is currently under clinical investigation.
Podona
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T
Laboratoire de Chimie Bioorganique et Analytique, associé au CNRS, Université d'Orléans, France.
Guardiola-Lemaître
B
B
Caignard
D H
DH
Adam
G
G
Pfeiffer
B
B
Renard
P
P
Guillaumet
G
G
D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D010856:Columbidae; D066298:In Vitro Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D014151:Anti-Anxiety Agents; D001578:Benzopyrans; D011985:Receptors, Serotonin; C088154:3,4-dihydro-3-amino-2H-1-benzopyran