Synthesis, Ligand Binding, and QSAR (CoMFA and Classical) Study of 3.beta.-(3'-Substituted phenyl)-, 3.beta.-(4'-Substituted phenyl)-, and 3.beta.-(3',4'-Disubstituted phenyl)tropane-2.beta.-carboxylic Acid Methyl Esters

Abstract

Several new 3 beta-(4'-substituted phenyl)-, 3-beta-(3'-substituted phenyl)-, and 3 beta-(3',4'-disubstituted phenyl)tropane-2 beta-carboxylic acid methyl esters were prepared and assayed for inhibition of [3H]WIN 35,428 binding to the dopamine transporter. The 3 beta-(3',4'-dichloro) and 3 beta-(4'-chloro-3'-methyl) analogues (2w and 2y; RTI-111 and RTI-112, respectively) with IC50 values of 0.79 and 0.81 nM showed the highest affinity. The contributions of quantitative structure-activity relationship (QSAR) models derived from the classical and comparative molecular field analysis (CoMFA) approaches to rational drug design were examined. CoMFA models were derived using steric and electrostatic potentials with SYBYL default values while the classical models were derived from pi and MR parameters. Using a 12-compound training set, both models were used for predicting the binding affinity of compounds both inside and outside the training set. The CoMFA study provided new insight into the steric and electrostatic factors influencing binding to the DA transporter and provided additional support for our original finding that CoMFA is useful in predicting and designing new compounds for study. The classical QSAR models, which were easier to obtain, suggest that the distribution property (pi) of the compounds is an important factor. Overall, the SAR, CoMFA, and conventional QSAR studies elaborated some features of the cocaine binding site pharmacophore and provided useful predictive information.

Distinct Molecular Recognition of Psychostimulants by Human andDrosophilaSerotonin Transporters

“…In rank order of potency, the iodine-containing compound RTI-55 is most potent, followed by the chlorine-containing (RTI-31) and then the fluorine-containing analog (␤-CFT). These results are similar to those reported in previous studies focused on the cocaine binding site in purified rat brain striatum, a rich source of dopaminergic neurons (Carroll et al, 1994). This study, although performed on tissue containing DAT, supports the hypothesis that the importance of the substitution at the 4Ј-position may be general for high-affinity 3-phenyltropane analog interactions with biogenic amine neurotransmitter transporters (Carroll et al, 1994).…”

“…The most potent 3-phenyltropane analog tested in this study at both hSERT and dSERT was RTI-55 (Carroll et al, 1994), whereas RTI-55, RTI-142, and cocaine are equipotent at the H 1-281 D 282-476 H 477-638 chimera. The 3-phenyltropane analog RTI-55 differs from cocaine in two ways.…”

“…All other chemicals were purchased from Sigma-Aldrich or Fischer Scientific (Pittsburgh, PA) and were of the highest grade available. 3-Phenyltropane analogs RTI-142 and RTI-121 (Neumeyer et al, 1994), RTI-55 and RTI-112 (Carroll et al, 1994), ␤-CFT (Neumeyer et al, 1996), RTI-32 (Holmquist et al, 1996), RTI-31 (Carroll et al,1995), RTI-83 (Blough et al, 1996), and RTI-311 (Scheffel et al, 1997) were synthesized as described previously. Substituted amphetamines were synthesized using conventional methodologies and their structures confirmed with NMR, mass spectrometry, and elemental analysis, all of which matched expected criteria.…”

“…To test this hypothesis, we have used a library of 3-phenyltropane analogs and substituted amphetamines to examine structural components of these compounds that are critical for recognition by hSERT, dSERT, and the H The results of these assays were used as input for modeling using CoMFA. CoMFA has proven valuable in previous studies as a method to model protein-ligand interactions in systems that lack protein crystal structures or other definitive structural information (Carroll et al, 1994;Wilcox et al, 1998;Li et al, 1999;Newman et al, 1999). The six models presented here indicate differences in recognition on four levels.…”

Effects of Dopamine Transporter Inhibitors on Cocaine Self-Administration in Rhesus Monkeys: Relationship to Transporter Occupancy Determined by Positron Emission Tomography Neuroimaging

“…Cocaine HCl (National Institute on Drug Abuse, Rockville, MD), [3␤-(4-chlorophenyl)tropane-2␤-(3-phenylisoxazol-5-yl)] HCl (RTI-177), and [(Ϫ)-3␤-(3Ј-methyl-4-chlorophenyl)tropane-2␤-carboxylic acid methyl ester] tartrate (RTI-112) were synthesized as reported previously (Carroll et al, 1992;Kotian et al, 1995) (Goodman et al, 2000).…”