A. Dolmella et al., Molecular modeling, theoretical calculations and property evaluation of three muscarinic agonists, X-ray structures of LU 25-109 and WAL 2014, J MOL STRUC, 526, 2000, pp. 287-301
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.
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