High-resolution NMR and computer modeling studies of the cannabimimetic aminoalkylindole prototype WIN-55212-2

Aminoalkylindoles (AAIs), although structurally dissimilar from the classic al cannabinoids (CCs), are known to be capable of binding to cannabinoid re ceptors and of evoking cannabimimetic responses. However, their mode of bin ding remains unknown, In this communication, we have carried out further st udies on the AAI prototype (R)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)meth yl] pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl] (1-naphthalenyl)methanone (WIN-5 5212-2, 1) by the combined use of high-resolution 2D NMR and computer model ing. Our results suggest that the minimum energy conformations of the molec ule 1 have distinct pharmacophoric features: (i) The naphthyl ring is orien ted off the plane of the benzoxazine ring by approximately 59 degrees with the carbonyl C=O group pointing toward the C2-CH3 group. (ii) At the C10-po sition the axial morpholinomethyl conformation is preferred over the equato rial in order to relieve a steric interaction with the C2-methyl group. The preferred conformer as defined by the three key pharmacophores, naphthyl, morpholino, and 3-keto groups, shows that the morpholinyl ring of the molec ule 1 deviates from the plane of the benzoxazine ring by about 32 degrees a nd orients in the left molecular quadrant. This model supports the hypothes is that a certain deviation of the morpholino group from the plane of the i ndole ring in compound 1 is essential for cannabimimetic activity. We postu late that such an alignment by the respective pharmacophores allows them to interact optimally with the receptor. The results should help us to better understand the pharmacophoric requirements of the AAIs and serve as a basi s for future SAR studies and drug design.