Role of channel activation in cognitive enhancement mediated by α7 nicotinic acetylcholine receptors

Abstract

Background and purpose: Several agonists of the a7 nicotinic acetylcholine receptor (nAChR) have been developed for treatment of cognitive deficits. However, agonist efficacy in vivo is difficult to reconcile with rapid a7 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. Experimental approach: Two structurally related a7 nAChR agonists were characterized and used to assess the degree of efficacy required in a behavioural paradigm. Key results: NS6784 activated human and rat a7 nAChR with EC50s of 0.72 and 0.88 mM, and apparent efficacies of 77 and 97% respectively. NS6740, in contrast, displayed little efficacy at a7 nAChR (<2% in oocytes, Յ8% in GH4C1 cells), although its agonist-like properties were revealed by adding a positive allosteric modulator of a7 nAChRs or using the slowly desensitizing a7V274T 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 and implications:Collectively, these findings suggest that a degree of a7 nAChR agonist efficacy is required for behavioural effects in the IA paradigm, and that such behavioural efficacy is not due to a7 nAChR desensitization. Also, a partial agonist of very low efficacy for this receptor could be used as an inhibitor, in the absence of a7 nAChR antagonists with favourable CNS penetration.

11C-NS14492 as a Novel PET Radioligand for Imaging Cerebral α7 Nicotinic Acetylcholine Receptors: In Vivo Evaluation and Drug Occupancy Measurements

“…In conscious monkeys, with a semiquantitative analysis the a 7 nAChR radioligand 11 C-CHIBA-1001 was not blocked to a significant extent by the structurally similar a 7 nAChR-selective partial agonist SSR180711 (9,13), and 11 C-(R)-MEQAA was blocked to an equal extent with SSR180711 as well as the 5-HT 3 antagonist ondansetron, indicating lack of in vivo selectivity with this compound (10). Similarly, we previously validated 11 C-NS12857 as a PET tracer for the a 7 nAChR; however, binding of this compound was also not blocked in vivo by either SSR180711 or the a 7 nAChR functional antagonist NS6740 (8,14). Recently, the a 7 nAChR PET radioligand 11 C-A-582941 was proposed to be displaceable by SSR180711 in a single conscious monkey (12), but no receptor occupancy was determined with this tracer.…”

Intrinsically Low Open Probability of α7 Nicotinic Acetylcholine Receptors Can Be Overcome by Positive Allosteric Modulation and Serum Factors Leading to the Generation of Excitotoxic Currents at Physiological Temperatures

“…Although our data caution against the therapeutic development of strong type II PAMs, in cases in which activation of the ␣7 ion channel is necessary for a desired therapeutic effect (Briggs et al, 2009), a type I PAM-based therapeutic approach might offer several potential advantages over agonistbased strategies. The temporal firing dynamics of native cholinergic signaling should be conserved because PAMs would theoretically only augment the response provided by endogenous agonists.…”

“…These observations support the hypotheses that ␣7 receptors may function in multiple ways and that various ligands differ in their ability to stimulate ion channel activation and/or signal transduction. Ligands such as GTS-21 and (1, 4-diazabicyclo[3.2.2]nonan-4-yl(5-(3-(trifluoromethyl)phenyl)-furan-2-yl)methanone (NS-6740) (Briggs et al, 2009), which are poor ion channel activators but are very effective for PNU-120596-induced activation of desensitized receptors (Papke et al, 2009), may also be effective for ion channel- molpharm.aspetjournals.org independent signal transduction. Much of the ␣7-mediated signal transduction data have come from studies of ␣7-mediated suppression of inflammation, and the low efficacy, strongly desensitizing agent GTS-21 has been shown to be very effective in several of these models (van Westerloo et al, 2006;Giebelen et al, 2007a,b;Pavlov et al, 2007;KageyamaYahara et al, 2008).…”

“…In cases in which activation of the ␣7 ion channel is necessary for a desired therapeutic effect (Briggs et al, 2009), a PAM-based therapeutic approach might offer several potential advantages over agonist-based strategies. However, a PAM-based strategy may also be subject to some potentially important limitations, especially if the potentiation of the calcium-permeable ␣7 receptor currents becomes so large that calcium homeostasis is disrupted, causing cell death (Orr-Urtreger et al, 2000;Lukas et al, 2001).…”

The Activity of GAT107, an Allosteric Activator and Positive Modulator of α7 Nicotinic Acetylcholine Receptors (nAChR), Is Regulated by Aromatic Amino Acids That Span the Subunit Interface

“…Presently, ␣7 receptors are being pursued as therapeutic targets for diverse indications such as Alzheimer disease, schizophrenia, and inflammatory diseases such as arthritis and asthma. However, it is unclear whether drugs optimized for these indications will work upon the receptors in the same ways, and it has been proposed that some ␣7-mediated effects, such as those related to cognition, require ion channel activation, although other functions may be ion channel-independent (6,7). nAChRs are allosteric proteins (8), and the conformational equilibrium among the resting, activated (i.e.…”