It is almost certain that the reinforcing effects of ethanol arise from a summation of its effects on a number of protein targets, likely including neurotransmitter receptors and ion channels. It would be highly beneficial for the treatment of alcoholism if these positively reinforcing effects of alcohol could be antagonized by chemical means and if novel anti-alcoholism compunds could be identified and developed rationally. In contrast, however, thus far medication development for the treatment of alcoholism has largely occurred serendipitously. For example, disulfuram (Antabuse) was originally being tested as an anti-parasitic compound by the Danish company Medicinalco when workers administered it noted symptoms of nausea following alcohol use. Rather than continuing to rely on serendipity for the discovery of new compounds to combat alcoholism it seems logical rather to attempt reasoned approaches in the identification of compounds that affect the functioning of protein targets that are believed (or that at least could) play roles in the reinforcing effects of ethanol. The research proposed in this R03 developmental application will attempt to identify peptides that selectively antagonize alcohol actions on the two protein targets we have selected for initial study: heteromeric 11/2 glycine receptors and heteromeric NR1/2B NMDA receptors. Based on the many different small molecules that are known to affect the functioning of receptors and ion channels (egs., polyamines, metals and benzodiazepines) there is a strong rationale to support the idea that small compounds can be identified that antagonize the actions of ethanol on the functioning of these ligand-gated ion channels. The receptors we chose to test in our studies were selected because they fulfilled all of the following criteria that we consider important for protein targets of potential interest: (1) they are proteins for which a substantial amount of evidence has accumulated regarding their importance for alcohol actions in vivo;(2) they exhibit considerable sensitivity to the effects of alcohol in vitro;and (3) we have expertise in the study of their function electrophysiologically
It is the purpose of this R03 developmental project to identify novel molecules that can affect the functioning of cell-surface proteins thought to be significant mediators of the effects of ethanol in vivo. The ultimate goal is the eventual development of compounds that can antagonize the reinforcing properties of alcohol, thus decreasing ethanol consumption in alcoholics. This rational approach to drug discovery contrasts markedly with the serendipitous approach to the discovery of drugs currently used in the treatment of alcoholism.
| Tipps, Megan E; Iyer, Sangeetha V; John Mihic, S (2012) Trifluoroacetate is an allosteric modulator with selective actions at the glycine receptor. Neuropharmacology 63:368-73 |
| Kirson, Dean; Todorovic, Jelena; Mihic, S John (2012) Positive allosteric modulators differentially affect full versus partial agonist activation of the glycine receptor. J Pharmacol Exp Ther 342:61-70 |
| Tipps, Megan E; Lawshe, Jessica E; Ellington, Andrew D et al. (2010) Identification of novel specific allosteric modulators of the glycine receptor using phage display. J Biol Chem 285:22840-5 |
