Optimization of allosteric modulators of nicotinic receptors
Principal Investigator: Kelvin W Gee
Affiliation: University of California
Abstract: Recent clinical and genetic studies provide strong evidence that spontaneous auditory gating deficits found in patients with schizophrenia maybe influenced by a7 nicotinic-acetylcholine receptors (nAChRs) located in the CA3 region of the hippocampus. Deficits in this auditory/sensory gating manifest as a sensory overload experience that can exacerbate both the positive and negative symptoms of schizophrenia. The human form of the auditory deficit is characterized by incomplete inhibitory processing of paired auditory evoked potentials spaced 50ms apart (P50). The P50 auditory deficit is genetically linked to the a7 nAChR locus on chromosome 15. Moreover, post-mortem analyses of schizophrenic brains indicate significant reductions in a7 nAChRs compared to normal individuals. The P50 auditory deficit is sensitive to cholinergic agents such as non-selective agonists (e.g., nicotine) and the selective a7 nAChRs agonist DMXB-A (GTS-21). In animal models, sensitivity to non-selective or selective a7 nAChR agonists is also blocked by selective a7 nAChR antagonists such as methyllycaconitine (MLA) or a-bungarotoxin but not a4¿2 selective antagonists such as dihydro-¿-ethroidine (DH¿E). The rodent P20-N40 auditory evoked potential (AEP) is analogous to the human P50 AEP and is a relevant model for assessing the effects of various pharmacological agents that may have utility to treat the sensory gating deficits of schizophrenia. Recent evidence using a rodent model of auditory gating deficit indicates that selective allosteric modulators of a7 nAChRs may boost the sensitivity of a7 nAChRs so that the gating deficit is rectified. However, the representative molecule in these proof-of-principle studies (PNU-120596) suffers from several attributes that make it unattractive as a therapeutic candidate. PNU-120596 is an allosteric modulator of a7 nAChRs which significantly alters the native kinetic response to agonist such that, in the presence of PNU-120596, a population of a7 nAChRs desensitized by high concentrations of nicotine can be re-sensitized. This is problematic since a7 nAChRs regulate Ca++ conductance. A large and sustained influx of Ca++ caused by the chronic presence of PNU-120596 in a treatment regimen is predicted to be neurotoxic. In contrast, our laboratory has developed selective a7 nAChR positive allosteric modulators which potentiate and preserve the native kinetics of receptor activation such that upon extended exposure to our compound desensitized a7 nAChRs remain as such. While the issue of retaining native kinetics of channel activity has been accomplished by our drug discovery efforts, we are uncertain as to what level of a7 nAChR efficacy is appropriate for therapeutic benefit in a setting where a7 nAChR function is already suboptimal (e.g., schizophrenia) while simultaneously avoiding Ca++-related neurotoxicity. The goal of the proposed research is to determine what minimum level of positive allosteric efficacy at a7 nAChRs is required to produce a reversal of P20-N40 auditory gating deficits in the DBA/2 mouse model of schizophrenia where a7 nAChR function is intrinsically compromised. Candidate molecules will be synthesized and tested in electrophysiological assays for enhancement of a7 nAChR currents elicited by nicotine to determine the structure activity relationships for maximum efficacy and potency relative to nicotine. The proposed molecules will show positive modulation of a7 nAChRs without activation of other nAChR subtypes (e.g., a4¿2, a3¿4) or other cys-loop ligand-gated ion channels (GABAA, 5HT3A). The pharmacokinetic (PK) profile of candidate molecules that fulfill our selection criteria for receptor subtype selectivity, potency and efficacy will be evaluated for whether appropriate brain levels (i.e., corresponding to maximum enhancement by the positive allosteric modulator observed in vitro) can be achieved. Completion of the proposed studies will establish the minimum extent of modulation of cholinergic transmission via a7 nAChRs necessary to correct a deficit of sensory inhibition in an animal model of schizophrenia. These results will help guide the pre-clinical development of potential candidate therapeutic agents that will be tested in schizophrenia and other neurological disorders (e.g., ADHD, Alzheimer's and other diseases involving cognitive deficit) that may be amenable to selective positive modulation of a7 nAChRs.
Funding Period: 2007-05-09 - 2009-04-30
more information: NIH RePORT