Varenicline: an alpha4beta2 nicotinic receptor partial agonist for smoking cessation.
Herein we describe a novel series of compounds from which varenicline (1, 6,7,8,9-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine) has been identified for smoking cessation. Neuronal nicotinic acetylcholine receptors (nAChRs) mediate the dependence-producing effects of nicotine. We have pursued alpha4beta2 nicotinic receptor partial agonists to inhibit dopaminergic activation produced by smoking while simultaneously providing relief from the craving and withdrawal syndrome that accompanies cessation attempts. Varenicline displays high alpha4beta2 nAChR affinity and the desired in vivo dopaminergic profile.
Coe
Jotham W
JW
Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340, USA. jwcoe@pfizer.com
Brooks
Paige R
PR
Vetelino
Michael G
MG
Wirtz
Michael C
MC
Arnold
Eric P
EP
Huang
Jianhua
J
Sands
Steven B
SB
Davis
Thomas I
TI
Lebel
Lorraine A
LA
Fox
Carol B
CB
Shrikhande
Alka
A
Heym
James H
JH
Schaeffer
Eric
E
Rollema
Hans
H
Lu
Yi
Y
Mansbach
Robert S
RS
Chambers
Leslie K
LK
Rovetti
Charles C
CC
Schulz
David W
DW
Tingley
F David
FD
O'Neill
Brian T
BT
D000818:Animals; D001552:Benzazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D018722:Nicotinic Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000502:physiology; D016540:Smoking Cessation / Q000379:methods*; D000068580:Varenicline; D014982:Xenopus laevis
D001552:Benzazepines; D018722:Nicotinic Agonists; D011810:Quinoxalines; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D000068580:Varenicline