Synthesis, potency, and in vivo evaluation of 2-piperazin-1-ylquinoline analogues as dual serotonin reuptake inhibitors and serotonin 5-HT1A receptor antagonists.
On the basis of the previously reported clinical candidate, SSA-426 (1), a series of related 2-piperazin-1-ylquinoline derivatives 3-16 were synthesized and evaluated as dual-acting serotonin (5-HT) reuptake inhibitors and 5-HT1A receptor antagonists. In particular, compound 7 exhibits potent functional activities at both the 5-HT transporter and 5-HT1A receptor, good selectivity over the alpha1-adrenergic and dopaminergic receptors, acceptable pharmacokinetic properties, and a favorable in vivo profile.
Zhou
Dahui
D
Chemical Sciences, Wyeth Research, CN 8000, Princeton, New Jersey 08543, USA. zhoud@wyeth.com
Stack
Gary P
GP
Lo
Jennifer
J
Failli
Amedeo A
AA
Evrard
Deborah A
DA
Harrison
Boyd L
BL
Hatzenbuhler
Nicole T
NT
Tran
Megan
M
Croce
Susan
S
Yi
Soo
S
Golembieski
Jeannette
J
Hornby
Geoffrey A
GA
Lai
Margaret
M
Lin
Qian
Q
Schechter
Lee E
LE
Smith
Deborah L
DL
Shilling
Adam D
AD
Huselton
Christine
C
Mitchell
Paul
P
Beyer
Chad E
CE
Andree
Terrance H
TH
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D065607:Cytochrome P-450 Enzyme Inhibitors; D006801:Humans; D017551:Microdialysis; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D011954:Receptors, Dopamine / Q000378:metabolism; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000928:Antidepressive Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D010879:Piperazines; D011804:Quinolines; D018340:Receptors, Adrenergic, alpha-1; D011954:Receptors, Dopamine; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors