Pharmacophore models of group I and group II metabotropic glutamate receptor agonists. Analysis of conformational, steric, and topological parametersaffecting potency and selectivity

A wide variety of conformationally constrained glutamate analogues, active as group I or group II metabotropic glutamate receptor agonists, were emplo yed in a molecular modeling study aimed at the definition of group I and gr oup II agonist pharmacophoric models. The results of this study can be summ arized as follows: (i) Recognition sites of both group I and group II mGluR s can adequately be described by five-point pharmacophores. (ii) An extende d conformation of glutamate is required for interaction with both group I a nd group II mGluRs. Group I receptors, however, can also be activated by a more folded conformation if only four pharmacophore points are considered. (iii) Conformational preferences are, however, not sufficient to explain th e potency and selectivity of the whole set of ligands. Volume comparison an alysis allowed us to define steric environments for group I and group II mG luRs. Group I mGluRs are characterized by a region of allowed volume in pro ximity of the distal acidic function, whereas group II mGluRs are character ized by a small polar pocket whose occupancy confers high potency and selec tivity. Finally, our study points out the necessity of a careful analysis o f the energetic requirements needed to attain the putative bioactive confor mations and of explicitly considering the conformational mobility of carbox ylate groups.