Nicotinic Pharmacophore Models

The arrow points to Q79 in loop D of the a7 subunit and the corresponding amino add residues of vertebrate and insect non-a subunits. 

For example, in 1970 a useful nicotinic pharmacophore model was already described by Beers and Reich and subsequently improved by Sheridan et al. [103]. Starting from different models a distance from the onium group to a point on the van der Waals surface of the H-bond acceptor of 5.9 A was common to several ligands. Up to now three binding models of neonicotinoids have been proposed (cf Fig. 29.1.2) [104]. 

On the other hand, Kagabu proposed that the nitrogen atom at the 1-position of the imidazolidine ring of 7 and one of the oxygen atoms of the nitro group within the [=N-N02]-pharmacophore (at the van der Waals surface) play an important role in the interaction with the binding sites on nAChR (Fig. 29.1.2b, cf. Model 

Thus the 7t-conjugated system composed of a N-nitro-imino- or N-cyano-imino group and the conjugated nitrogen in 1-position are considered essential moieties for the binding of neonicotinoids to the putative cationic subsite in insect nAChR. 

The third and most recent model III (Fig. 29.1.2b) involves a crucial role for the N-nitro group within the [=X-N02]-pharmacophore, an important contribution from the 6-chloro-pyrid-3-yl ring nitrogen, and a supplemental role for the nitrogen in 1-position. A first confirmation of this model III is exemplified by interaction of 7 with the a7 nAChR, based on the AChBP [109]. 

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Figure 14.14. Example of pharmacophoric element selection for molecular modeling of nicotine. Pharmacophoric elements A and B are nitrogens and element C is on the nAChR receptor with which element B would optimally connect. Carbon, green nitrogen, light blue hydrogen attached to the basic nitrogen, white putative nAChR binding site, dark blue.

Structure-activity investigations of numerous natural products with high activity and as the profile of a partial agonist at the nicotinic a4P2-receptor provided a suitable pharmacophore model. This suggested a core structure with a basic nitrogen, which is protonated under physiological conditions, and in most cases an electron-deficient aromatic system, which is separated by two or three C-C bonds. 

Keywords Nicotinic acetylcholine receptor (nAChR) oic4p2 Nicotine Epibatidine Pyrrolizidine 2-azabicyclo[2.2.1 Jheptane Furo[2,3-h]pyridine Furo[3,2-b]pyridine Pharmacophore Pyridyl ether Furo[2,3-c]pyridine Furo[3,2-c]pyridine Molecular modelling... 

Figure 2. Nicotinic 3-D pharmacophore query based on the ensemble distance geometry derived model of Dixon et alP...

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