Role of channel activation in cognitive enhancement mediated by alpha7 nicotinic acetylcholine receptors.
OBJECTIVE
Several agonists of the alpha7 nicotinic acetylcholine receptor (nAChR) have been developed for treatment of cognitive deficits. However, agonist efficacy in vivo is difficult to reconcile with rapid alpha7 nAChR desensitization in vitro; and furthermore, the correlation between in vitro receptor efficacy and in vivo behavioural efficacy is not well delineated. The possibility that agonists of this receptor actually function in vivo as inhibitors via desensitization has not been finally resolved.


METHODS
Two structurally related alpha7 nAChR agonists were characterized and used to assess the degree of efficacy required in a behavioural paradigm.


RESULTS
NS6784 activated human and rat alpha7 nAChR with EC(50)s of 0.72 and 0.88 microM, and apparent efficacies of 77 and 97% respectively. NS6740, in contrast, displayed little efficacy at alpha7 nAChR (<2% in oocytes, < or =8% in GH4C1 cells), although its agonist-like properties were revealed by adding a positive allosteric modulator of alpha7 nAChRs or using the slowly desensitizing alpha7V274T receptor. In mouse inhibitory avoidance (IA) memory retention, NS6784 enhanced performance as did the 60% partial agonist A-582941. In contrast, NS6740 did not enhance performance, but blocked effects of A-582941.


CONCLUSIONS
Collectively, these findings suggest that a degree of alpha7 nAChR agonist efficacy is required for behavioural effects in the IA paradigm, and that such behavioural efficacy is not due to alpha7 nAChR desensitization. Also, a partial agonist of very low efficacy for this receptor could be used as an inhibitor, in the absence of alpha7 nAChR antagonists with favourable CNS penetration.
Briggs
Clark A
CA
Neuroscience Research, Abbott Laboratories, Abbott Park, IL, USA. briggs.clark@gmail.com
Grønlien
Jens Halvard
JH
Curzon
Peter
P
Timmermann
Daniel B
DB
Ween
Hilde
H
Thorin-Hagene
Kirsten
K
Kerr
Paige
P
Anderson
David J
DJ
Malysz
John
J
Dyhring
Tino
T
Olsen
Gunnar M
GM
Peters
Dan
D
Bunnelle
William H
WH
Gopalakrishnan
Murali
M
D000494:Allosteric Regulation; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D053961:Azabicyclo Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D002460:Cell Line; D003072:Cognition Disorders / Q000188:drug therapy / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D005663:Furans / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D018722:Nicotinic Agonists / Q000494:pharmacology*; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D010069:Oxadiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D014982:Xenopus laevis; D064569:alpha7 Nicotinic Acetylcholine Receptor
C547286:1,4-diazabicyclo(3.2.2)nonan-4-yl(5-(3-(trifluoromethyl)phenyl)furan-2-yl)methanone; C547287:2-(1,4-diazabicyclo(3.2.2)nonan-4-yl)-5-phenyl-1,3,4-oxadiazole; C524029:A-582941; D053961:Azabicyclo Compounds; C579167:Chrna7 protein, human; C579166:Chrna7 protein, mouse; C579165:Chrna7 protein, rat; D005663:Furans; D018722:Nicotinic Agonists; D010069:Oxadiazoles; D011724:Pyridazines; D011758:Pyrroles; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor