SYNTHESIS AND PHARMACOLOGY OF POTENTIAL COCAINE ANTAGONISTS .2. STRUCTURE-ACTIVITY RELATIONSHIP STUDIES OF AROMATIC RING-SUBSTITUTED METHYLPHENIDATE ANALOGS

As part of a program to develop medications which can block the bindin g of cocaine to the dopamine transporter, yet spare dopamine uptake, a series of aromatic ring-substituted methylphenidate derivatives was s ynthesized and tested for inhibitory potency in [H-3]WIN 35,428 bindin g and [H-3]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 com pounds were much less potent than the corresponding meta- and/or para- substituted derivatives. The most potent compound against [H-3]WIN 35, 428 binding, m-bromo-TMP, was 20-fold more potent than the parent comp ound, whereas the most potent compound against [H-3]dopamine uptake, m ,p-dichloro-TMP, was 32-fold more potent. Three derivatives with m- or p-halo substituents were more potent than TMP, while electron-donatin g substituents caused little change or a small loss of potency. All of the derivatives had Hill coefficients approaching unity, except mg-di chloro-TMP, which had an n(H) of 2.0. Although the potency of the (+/- )methylphenidate derivatives in the two assays was highly correlated ( R(2) = 0.986), the compounds m-chloro-, m-methyl-, and p-iodo-TMP were 4-5-fold more potent at inhibiting [H-3]-WIN 35,428 binding than [H-3 ]-dopamine uptake (cocaine has a ratio of 2.3). These and other compou nds may be promising candidates for further testing as potential parti al agonists or antagonists of cocaine.