Hallucinogens belong to various chemical classes, including indolylalkylamines (e.g., psilocin), ergolines (e.g., LSD), and phenylalkylamines (e.g., mescaline, and the substituted amphetamines DOM and DOET); even small structural changes within each class profoundly affect their pharmacology. Methods and approaches of theoretical chemistry will therefore be used to express the molecular determinants for the actions of these drugs on receptors in terms of molecular properties rather than atomic structures. Molecular determinants are selective for each receptor; with special attention to receptors and binding sites of 5-hydroxytryptamine (5-HT), the molecular determinants leading from receptor recognition to receptor activation by hallucinogens will be characterized with a proton transfer model (PTM) we developed to model recognition and activation. The model will be probed by simulations with known 5-HT agonists and antagonists, including hallucinogens. Computerized searches through crystallographical data banks will be used to identify PTM-like structures in proteins; such naturally occurring molecular arrangements that can be triggered by interaction with 5-HT analogs will be incorporated in simulations of receptor activation. Metalloenzymes, chosen because coordinates are available from crystallography both for the native enzymes and for complexes with a variety of ligands, will serve as heuristic models in which the structure of both the """"""""receptor"""""""" and the """"""""drug"""""""" are known, to test the approaches we use for their reliability and predictive power. Methods of quantum chemistry (i.e., ab-initio and pseudopotential calculations of wavefunctions, and calculations of properties dependent on the electron density distribution such as its moments, the molecular electrostatic potential, etc.), will be used to calculate the drugs, their properties, and to simulate interactions with receptor models. Molecular mechanics and some semiempirical approximations will be applied, together with macromolecular structure analysis and molecular modeling, to study the enzyme-ligand interactions. In collaborative studies, inferences from the theoretical work, as well as newly designed compounds, will be tested by our colleagues on a variety of 5-HT receptors and binding sites; results from studies with site-directed reagents used to identify the functional groups involved in binding of the compounds will further probe the results from theory and provide new working hypotheses for discrete mechanisms of action of hallucinogens on receptors.
| Shenker, A; Maayani, S; Weinstein, H et al. (1987) Pharmacological characterization of two 5-hydroxytryptamine receptors coupled to adenylate cyclase in guinea pig hippocampal membranes. Mol Pharmacol 31:357-67 |
| Liebman, M N; Venanzi, C A; Weinstein, H (1985) Structural analysis of carboxypeptidase A and its complexes with inhibitors as a basis for modeling enzyme recognition and specificity. Biopolymers 24:1721-58 |
| Shenker, A; Maayani, S; Weinstein, H et al. (1985) Two 5-HT receptors linked to adenylate cyclase in guinea pig hippocampus are discriminated by 5-carboxamidotryptamine and spiperone. Eur J Pharmacol 109:427-9 |
