Synthesis, ligand binding, QSAR, and CoMFA study of 3.beta.-(p-substituted phenyl)tropane-2.beta.-carboxylic acid methyl esters

Abstract

A series of 3 beta-(p-substituted phenyl)tropane-2 beta-carboxylic acid methyl esters (2) were synthesized and found to possess high affinity for the cocaine binding site in rat striatum. The p-chloro (2c) and p-iodo (2n) compounds, which were the most potent analogues prepared, were found to be 85 and 78 times more potent than (-)-cocaine. The p-bromo (2m) and p-methyl (2d) were also 56 and 60 times more potent than cocaine. QSAR and CoMFA studies were conducted to correlate binding affinity of the cocaine analogues with their structural features. Whereas the QSAR study gave relatively low correlations, the CoMFA study gave a correlation with high predictive value.

Distinct Molecular Recognition of Psychostimulants by Human andDrosophilaSerotonin Transporters

“…The potency of the compounds increases when going from F-, to Cl-, to I-, with increasing hydropho- jpet.aspetjournals.org bicity of substituents. Steric bulk effects have also been observed for DAT binding sites in rat striatum, where a 4Ј-bromo substitution had similar potency as a 4Ј-methyl substitution (1.8 versus 1.7 nM) (Carroll et al, 1991). Similar van der Waals radii of the bromine and methyl substituent could explain the similarity in potency.…”

Computational and Biochemical Docking of the Irreversible Cocaine Analog RTI 82 Directly Demonstrates Ligand Positioning in the Dopamine Transporter Central Substrate-binding Site

“…Intensive efforts to understand the basis for cocaine interaction with DAT, NET, and SERT have relied on site-directed mutagenesis (SDM), substituted cysteine accessibility method (SCAM) (44 -47), and quantitative structure activity relationship (QSAR) of ligand pharmacophores (48,49). Many studies support the formation of a salt bridge between the conserved Asp residue in the unwound region of TM1 and the positively charged tropane nitrogen of cocaine, suggesting that cocaine binds near S1 and competes with substrate for interaction at this crucial site (31,37,38,44,47,50).…”

“…1) (50). RTI 82, cocaine, and the commonly used cocaine analog (Ϫ)-2␤-carbomethoxy-3␤-(4-fluorophenyl)tropane (CFT) share a common pharmacophore consisting of the tropane ring and 3␤-phenyl group that direct high affinity binding (48,49). All of these compounds bind noncovalently to DAT, but [ 125 I]RTI 82 contains a photoactivatable 4Ј-azido-3Ј-iodophenylethyl ester (AIP) moiety that forms a highly reactive singlet nitrene that reacts with C-H or N-H groups when the sample is irradiated with ultraviolet light, thus forming a covalent bond with the protein (61,62).…”

The Structure, Proton Affinity, Electrostatic Properties and Its Relation to Biological Activity of Cocaine and Its Derivatives.

“…Several structure-activity studies have been reported [3][4][5][6][7][8][9][10][11][12] which have concluded the requirements for the cocaine binding. This analysis leads to the following observations [1]:…”

“…Significant and important effects on activity are obtained by substitution at The structure-activity relation (SAR) data combined with some preliminary molecular modelling studies [6] allow speculation on a preliminary pharmacophore model for the cocaine receptor. All high-affinity cocaine ligands require the presence of a basic amino group which is involved in an electrostatic or hydrogen bonding interaction with the receptor protein.…”