RECOGNITION SITE MAPPING AND RECEPTOR MODELING - APPLICATION TO 5-HT RECEPTORS

A basic pharmacophore of the 5-HT1D agonist recognition site was defined from a conformation-activity relationship study of 11 different agonists. It consists of an aromatic ring and a nitrogen atom in well defined relative positions. The contribution of the other molecular components was also explored. Similarities and differences between the 5-HT1D and some other G-protein coupled receptor agonist, recognition sites were discussed. Following a different approach, three-dimensional models of the 5-HT2 and 5-HT1A receptor transmembrane region were defined from the analysis of their primary sequences, published site directed mutagenesis and labelling data and from the experimental structure of bacteriorhodopsin. Residues likely to be involved in 5-HT binding were proposed from the models of the receptor-neurotransmitter complexes. There is an excellent convergence between binding site models derived from ligands analysis and from receptor modelling.