Nicotinic receptors discovery

Blum LC, van Deursen R, Bertrand S et al (2011) Discovery of a7-nicotinic receptor ligands by virtual screening of the chemical universe database GDB-13. J Chem Inf Model 51(12) 3105-3112... 

Arneric SP, Holladay M, Williams M (2007) Neuronal nicotinic receptors a perspective on two decades of drug discovery research. Biochem Phtirmacol 74 1092-1101 Arora S, Anubhuti (2006) Role of neuropeptides in appetite regulation and obesity - A review. 

Holladay, M.W., Cosford, N.D.P., McDonald, I.A., 1999. Natural products as a source of nicotinic acetylcholine receptor modulators and leads for dmg discovery. In Americ, S.P., Brioni, J.D. (Eds.), Neuronal Nicotinic Receptors Pharmacology and Therapeutic Opportunities. Wiley-Liss, New York, pp. 253-270. 

Holladay MW, Dart MJ, Lynch JK. Neuronal nicotinic receptors as targets for drug discovery. J Med Chem 1997 40 4170-4194. 

The recent discovery that the mutation of (figure 4) affects the desensitization rate of the 5-HT3 receptor expressed in oocytes [102] is in favor of such a hypothesis, since similar results have been reported for the mutation of the corresponding residue in the nicotinic receptor alpha subunit [116], Interestingly, some point mutations in this Mil domain have also been shown to be associated with modifications in calcium permeability [122], which may explain the reported differences in its permeability for the 5-HTa receptor [95,97,98,102]. 

Gotti C, Riganti L, Vailati S, Clementi E (2006) Brain neuronal nicotinic receptors as new targets for drug discovery. Curr Pharm Des 12 407-428... 

Discovery of (R)-3-amino-1-(3-pyridinyl)-pyrrolidine, a neuronal nicotinic receptor agonist for the treatment of chronic pain... 

Fluorine has been used to modulate the basicity of amines which may lead to an improvement in brain exposure. Recently, the discovery of a series of a4(32 nicotinic acetylcholine receptor (nAChR) potentiators as possible treatment for Parkinson s disease and schizophrenia was were disclosed [40]. Optimization of isoxazole 40 included the bioisosteric replacement of the central amide by an imidazole ring. Introduction of a fluorine at the 6-position of the phenyl ring provided compound 41. This compound had excellent potency but was determined to be a substrate for P-gp (efflux ratio >10). In an attempt to reduce amine basicity and decrease the efflux propensity, the 4-fluoropiperidine 42 was identified which retained potency and had significantly reduced P-gp efflux liability (efflux ratio 1). CNS penetration of 42 was observed in rodents following intraperitoneal (IP) treatment at 5mg/kg and showed a brain concentration of 6.5 gM. 

The Road to Discovery of Neuronal Nicotinic Cholinergic Receptor Subtypes... 

Abstract The discovery that mammalian brain expresses the mRNAs for nine different nicotinic cholinergic receptor subunits (a2-a7, p2-p4) that form functional receptors when expressed in Xenopus laevis oocytes suggests that many different types of nicotinic cholinergic receptors (nAChRs) might be expressed in the mammalian brain,. Using an historical approach, this chapter reviews some of the... 

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