Mark Froimowitz

Further evidence for a dopamine reuptake pharmacophore. The effect of N-methylation on Threo-methylphenidate and its analogs

Abstract N-methyl derivatives of methylphenidate and four analogs were synthesized and assayed for affinity at the dopamine transporter. The binding affinities of the N-methyl compounds were consistently lower by a factor ranging from 4 to 30 as compared with the corresponding secondary amine. This is consistent with the predictions of a pharmacophore model of compounds that bind to the dopamine transporter.

Conformational analysis and a crystal structure of bupropion, an antidepressant with dopamine reuptake blocking activity.

A conformational analysis has been performed on the antidepressant bupropion using the MM3-92 program. In addition, the structure of the compound in the crystal state was obtained. There is good agreement between the computed global minimum and the structure observed by crystallography. The three-dimensional structure of the preferred conformer of bupropion is consistent with the three-dimensional structures of other dopamine reuptake blockers such as cocaine, CFT, and methylphenidate.

Crystal Structures of Analogs of threo-Methylphenidate

The crystal structures of the chloride salts of five analogs of threo-methylphenidate have been obtained. Four of these have different substituents on the phenyl ring while the fifth is the ethyl ester of methylphenidate. All five structures have similar three-dimensional conformations and these are compared with the global minimum obtained by MM2-87 calculations. There is good agreement between the crystal structures and the computed global minimum with the major difference being the presence of a chloride counterion in the crystal structures that prevents the carbonyl oxygen from approaching the equatorial ammonium hydrogen as closely as in the computed global minimum.

Solution- and Solid-State Conformations of C(α)-Alkyl Analogues of Methylphenidate (Ritalin) Salts: Avoidance of gauche+gauche– Interactions

Alkyl analogues of methylphenidate (Ritalin) salts are slow onset, long duration dopamine reuptake inhibitors with a potential use as a cocaine abuse pharmacotherapy. X-ray crystallographic studies and nuclear magnetic resonance (NMR) investigations strongly suggest that avoidance of sterically unfavorable gauche(-)gauche(+) orientations effectively influences both the C(α)-alkyl side chain conformation and the formation of a predominant rotamer about the CH-CH bond ligating piperidine and C(Ar)R moieties. The favored CH-CH rotamer in D(2)O and in CD(2)Cl(2) of the pharmacologically interesting i-Bu and CH(2)-cyc-Pnt (RS,RS)-salts has the same antiperiplanar arrangement that was found in the crystal structures, although there clearly is a fast equilibrium involving smaller amounts of synclinal partners. While the rotamer in the (RS,SR)-i-Bu HCl crystal structure exhibits a synclinal orientation for the vicinal pair of adjacent methine protons, the weighted time-averaged arrangement for these protons becomes almost completely antiperiplanar when the crystals are dissolved in D(2)O. Increased steric congestion around the CH-CH bond in the analogous N-methyl tertiary ammonium salts seems to augment the quantity of the preferred rotamer within the mixture. The stereochemistry of the species observed via NMR seems to arise from specific combinations of N-methyl orientation and avoidance of sterically unfavorable gauche(-)gauche(+) arrangements.

CTDP-32476: A Promising Agonist Therapy for Treatment of Cocaine Addiction.

Agonist-replacement therapies have been successfully used for treatment of opiate and nicotine addiction, but not for cocaine addiction. One of the major obstacles is the cocaine-like addictive potential of the agonists themselves. We report here an atypical dopamine (DA) transporter (DAT) inhibitor, CTDP-32476, that may have translational potential for treating cocaine addiction. In vitro ligand-binding assays suggest that CTDP-32476 is a potent and selective DAT inhibitor and a competitive inhibitor of cocaine binding to the DAT. Systemic administration of CTDP-32476 alone produced a slow-onset, long-lasting increase in extracellular nucleus accumbens DA, locomotion, and brain-stimulation reward. Drug-naive rats did not self-administer CTDP-32476. In a substitution test, cocaine self-administration rats displayed a progressive reduction in CTDP-32476 self-administration with an extinction pattern of drug-taking behavior, suggesting significantly lower addictive potential than cocaine. Pretreatment with CTDP-32476 inhibited cocaine self-administration, cocaine-associated cue-induced relapse to drug seeking, and cocaine-enhanced extracellular DA in the nucleus accumbens. These findings suggest that CTDP-32476 is a unique DAT inhibitor that not only could satisfy ‘drug hunger’ through its slow-onset long-lasting DAT inhibitor action, but also render subsequent administration of cocaine ineffectual—thus constituting a novel and unique compound with translational potential as an agonist therapy for treatment of cocaine addiction.