It is well established that hippocampal cholinergic neurotransmission plays an important role in learning and memory. Disorders of learning and memory such as Alzheimer's disease (AD) and dementia have been associated with a reduction in cholinergic neurotransmission in hippocampus. Specifically, expression of the nicotinic acetylcholine receptor (nAChR) subtype a4b2 is dramatically reduced in these disorders, while the a7 subtype is relatively preserved. A variety of drug-discovery efforts are focused on creation of molecules that will increase nicotinic neurotransmission with the hope that these molecules will increase cognition in the dementias. In addition to the nicotinic system, GABAA receptors containing the a5 subunit (GABAA a5 receptors) can modulate hippocampal neurotransmission. Selective inhibition of GABAA a5 receptor function in the hippocampus promotes an elevated state of cognition in animal models of learning and memory, suggesting that inhibition of GABAA a5 may also be a viable therapeutic strategy. Like a7 nAChRs, GABAA a5 receptors are reported to be relatively spared in conditions like mild AD. These observations suggest that two important therapeutic targets that subserve learning and memory are present in AD brains and could be targeted simultaneously. A molecule discovered in our lab is a selective negative allosteric modulator of GABAA a5 receptors AND a positive allosteric modulator of a7 nAChRs. This molecule, termed 2-228, represents the first known compound with putative cognition enhancing properties derived from simultaneous allosteric modulation of both GABAA and nACh receptors. The goal of the proposed research is to develop a positive allosteric modulator of a7 nAChRs that is also a negative allosteric modulator of GABAA a5 receptors with more drug-like attributes than 2-228. The proposed molecule will show positive modulation of a7 nAChRs without activation of other nAChR subtypes (e.g., a4b2, a3b4). The proposed molecule will also show partial negative allosteric modulation of GABAA a5 receptors with no efficacy at GABAA a1, a2, or a3 subunit containing receptors. The structure activity relationships of 2-228 and its analogs will be deduced by measuring their electrophysiological activity at various GABAA and nACh receptor subunits expressed in Xenopus oocytes. The pharmacokinetic (PK) profile of up to 5 candidate molecules that fulfill our selection criteria for receptor subtype selectivity, potency and efficacy will be evaluated for improved bioavailability over 2-228 in rodent models. Completion of the proposed studies will yield a suitable candidate(s) that will be the topic of future studies to characterize their in vitro and in vivo pharmacology and site of action, with the ultimate goal of developing a novel drug(s) for the treatment of cognitive deficits associated with AD and other senile dementias. ? ? ?
| Johnstone, Timothy B; Gu, Zhenglin; Yoshimura, Ryan F et al. (2011) Allosteric modulation of related ligand-gated ion channels synergistically induces long-term potentiation in the hippocampus and enhances cognition. J Pharmacol Exp Ther 336:908-15 |
