NAChR agonistic binding site

Because a crystal structure of nAChR is not available, the nAChR agonist binding site remains unknown. Nevertheless, the pharmacophore models and ir-cation studies should provide valuable guidance in the design of more selective and potent nAChR agonists for the treatment of CNS-related diseases. 

Figure 4. Homology model of the wild-type and T77R R79V double mutant of the chicken a4p2 nAChR agonist binding site with imidacloprid bound. Reproduced from reference [21] with permission of American Society for Pharmacology and Experimental Therapeutics.

Early studies of muscle nAChRs established that the receptor has two agonist binding sites and both must be occupied for efficient channel opening to occur. 

Papke RL, Jacobs LB, Stokes C (2007) Activation of alpha7 nAChR occurs with low fractional occupancy of the agonist binding sites. Soc Neurosci Abst 37 574.9 Pauly JR, Marks MJ, Gross SD, Collins AC (1991) An autoradiographic analysis of cholinergic receptors in mouse brain after chronic nicotine treatment. J Pharmacol Exp Ther 258 1127-1136... 

A number of aromatic amino acids have been identified near the agonist-binding site of the nAChR, which suggests that... 

Several investigations have identified key interactions that lead to the binding of small molecules such as ACh, (S)-(—)-nicotine (1) and (—)-epibatidine (16) (cf. Fig. 29.1.2 below) at the agonist-binding site of nAChRs [71]. 

Structurally, nAChRs are comprised of homologous or heterologous combinations of five polypeptide subunits. Each subunit is composed of four transmembrane (TM 1 ) domains arranged around a central, water-filled pore. The extracellular N-terminal domain of each of the five subunits makes up the agonist binding site [35]. The pentameric nAChR, formed by various combinations of a and p subunits, is widely distributed in mammalian brain [36, 37]. Eight forms of the a subunit (ot2-otlO) and three forms of the p subunit (p2-p4) have been identified. The mechanism for the neuroprotective/trophic effects of nicotine is not known but seems to be multifaceted, as the reader will appreciate throughout this chapter. 

Agonists activate nAChR by binding to the agonistbinding site (Fig. 1). They can remain bound (often with higher affinity) when the nAChR enters the desensitised state. 

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