1,9-Alkano-bridged 2,3,4,5-tetrahydro-1H-3-benzazepines with affinity for the alpha 2-adrenoceptor and the 5-HT1A receptor.
A number of 1,9-alkano-bridged 2,3,4,5-tetrahydro-1H-3-benzazepines were prepared and evaluated for 5-HT1A receptor and alpha 2-adrenoceptor affinity by using radioligand receptor binding techniques. Several compounds displayed 5-HT1A receptor affinity comparable to, or greater than, the known 5-HT1A ligand buspirone. The highest affinity 5-HT1A receptor ligands were N-alkyl-, N-allyl-5-chloro-, and 5-methoxy-1,2,3,4,8,9,10,10a-octahydronaphth[1,8-cd]azapines (4c, 4m, 4n), which had pKi values of 7.9-8.1. The S enantiomer of 4c had a higher affinity for the 5-HT1A receptor than the corresponding R isomer (pKi of 8.2 for (S)-4c vs 7.7 for (R)-4c). These compounds had a relatively low affinity for the alpha 2-adrenoceptor (pKi of 7 or less). On the other hand, the closely related 5-chloro-2-methyl-2,3,4,8,9,9a-hexahydro-1H-indeno[1,7-cd]azepine (3b) had high affinity for both the alpha 2-adrenoceptor (pKi = 8.1) and 5-HT1A receptor (pKi = 7.6). These results indicate that the two receptors may share common recognition sites.
Clark
R D
RD
Institute of Organic Chemistry, Syntex Research, Palo Alto, California 94304.
Weinhardt
K K
KK
Berger
J
J
Fisher
L E
LE
Brown
C M
CM
MacKinnon
A C
AC
Kilpatrick
A T
AT
Spedding
M
M
D000818:Animals; D001552:Benzazepines / Q000138:chemical synthesis* / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D002627:Chemistry, Physical; D066298:In Vitro Techniques; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D001552:Benzazepines; D011942:Receptors, Adrenergic, alpha; D011985:Receptors, Serotonin