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Synthesis and Pharmacology of Potential Cocaine Antagonists. 2. Structure-Activity Relationship Stud

Synthesis and Pharmacology of Potential Cocaine Antagonists. 2. Structure-Activity Relationship Stud

  1. NeuroChi
    As part of a program to develop medications which can block the binding of cocaine to the
    dopamine transporter, yet spare dopamine uptake, a series of aromatic ring-substituted
    methylphenidate derivatives was synthesized and tested for inhibitory potency in [3H]WIN
    35,428 binding and [3H]dopamine uptake assays using rat striatal tissue. Synthesis was
    accomplished by alkylation of 2-bromopyridine with anions derived from various substituted
    phenylacetonitriles. In most cases, erythro compounds were markedly less potent than the
    corresponding (()-threo-methylphenidate (TMP; Ritalin) derivatives. The ortho-substituted
    compounds were much less potent than the corresponding meta- and/or para-substituted
    derivatives. The most potent compound against [3H]WIN 35,428 binding, m-bromo-TMP, was
    20-fold more potent than the parent compound, whereas the most potent compound against
    [3H]dopamine uptake, m,p-dichloro-TMP, was 32-fold more potent. Threo derivatives with mor
    p-halo substituents were more potent than TMP, while electron-donating substituents caused
    little change or a small loss of potency. All of the derivatives had Hill coefficients approaching
    unity, except m,p-dichloro-TMP, which had an nH of 2.0. Although the potency of the (()-
    methylphenidate derivatives in the two assays was highly correlated (R2 ) 0.986), the
    compounds m-chloro-, m-methyl-, and p-iodo-TMP were 4-5-fold more potent at inhibiting [3H]-
    WIN 35,428 binding than [3H]dopamine uptake (cocaine has a ratio of 2.3). These and other
    compounds may be promising candidates for further testing as potential partial agonists or
    antagonists of cocaine.

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