Molecular modeling, theoretical calculations and property evaluation of three muscarinic agonists, X-ray structures of LU 25-109 and WAL 2014

LU 25-109 (II) and WAL 2014 (talsaclidine, III) are two M1 muscarinic agoni sts chemically related to the natural substance arecoline (I). All these co mpounds have beneficial effects on memory and cognition in animals and huma ns, and they have been proposed in the treatment of Alzheimer's disease, bu t only III will likely find a place in therapy. In this work we have invest igated the solid state structures of II and III and the X-ray structures of the two molecules and of the parent compound I have been used to input a s eries of computational chemistry efforts. In particular, the X-ray geometries have been manipulated to model 20 molec ular structures (1-20) which have been submitted to ab initio, semiempirica l quantum mechanics and molecular mechanics calculations. The conformationa l space accessible to the 20 structures has been assessed by means of poten tial energy maps. The reactivities of 1-20 have been estimated by examining at the graphics terminal the composition and the extension of the frontier orbitals (HOMOs and LUMOs) and of the molecular electrostatic potential. T he information obtained has been interpreted to explain the different degre es of activity shown by I-III. Our data indicate that III has better in viv o activity for its intermediate size, less polar surface, conformational ri gidity and orientation of reactive domains. (C) 2000 Elsevier Science B.V. All rights reserved.