Interactions between cocaine and -receptor (R) ligands suggest a role for Rs in the effects of cocaine. For example, this laboratory showed several years ago that the R antagonists, BMY 14802 and rimcazole, antagonized the locomotor-stimulant effects of cocaine at doses that were inactive when given alone, suggesting a specific antagonist effect. Several other R antagonists subsequently have been reported to block cocaines locomotor-stimulant effects, as well as its acute toxic effects. Further, an antisense oligodeoxynucleotide directed against Rs attenuated the locomotor and toxic effects of cocaine, providing more compelling evidence for a mediation by Rs of some of the effects of cocaine, including its acute toxic effects. In addition, these studies suggest compounds directed at Rs as potential cocaine-abuse medications. One study examined the novel R ligand, AC927 (1-(2-phenethyl)piperidine oxalate), as a potential antagonist of the behavioral and toxic effects of cocaine in laboratory animals. Acute administration of AC927 in male, Swiss Webster mice significantly attenuated cocaine-induced convulsions, lethality, and locomotor activity, at doses that alone had no significant effects on behavior. Sub-chronic administration of AC927 also attenuated cocaine-induced conditioned place preference in mice, at doses that alone had no effects on place conditioning. In drug-discrimination studies, AC927 partially substituted for the discriminative stimulus effects of cocaine. When it was administered with cocaine, AC927 shifted the cocaine dose-effect curve to the left, suggesting an enhancement of the discriminative-stimulus effects of cocaine. In non-human primates, AC927 was self-administered, maintaining responding that was intermediate between contingent saline and a maintenance dose of cocaine. The ability of AC927 to elicit some cocaine-like effects, and to also reduce many cocaine-induced behaviors suggests that it is a promising lead for the development of a medication to treat cocaine abuse. Previous studies from other laboratories of the interactions of R ligands with the reinforcing effects of cocaine have yielded complex results. Several studies reported dose-dependent antagonism of cocaine-induced place conditioning by R antagonists. In contrast, a selective R antagonist, BD 1047, failed to substantially affect rates of cocaine self-administration. In the same study, responding was established with food- or cocaine-reinforcement under one set of stimulus conditions, and extinguished under another. Subsequent restoration of the original stimulus conditions under extinction increased rates of responding (reinstatement). BD1047 attenuated the reinstatement of responding previously maintained by cocaine or food. The preferential effect of BD 1047 on cocaine reinstatement suggests a role for Rs in the abuse of cocaine, whereas the direct effects of BD 1047 on cocaine self-administration do not. In the course of studies on the role of the R in the reinforcing effects of cocaine, we found R agonists to produce a leftward shift in the cocaine self-administration dose-effect curve. Those findings lead to the assessment of the reinforcing effects of R agonists, and a further comparison of the effects of R agonists and antagonists in rats self-administering cocaine or R agonists. In the process we found reinforcing effects of the R agonists, DTG and PRE-084, and compared the pharmacology of cocaine and R agonist self-administration. The findings support an important role of Rs in the reinforcing effects of drugs, and previous suggestions for the development of drugs targeting Rs as medications for cocaine dependence. Previous studies from this laboratory found that rimcazole, a -receptor antagonist, also binds to the dopamine transporter with affinity comparable to its -receptor affinity. However, this drug exhibited neither cocaine-like psychomotor stimulant nor cocaine-like subjective effects in rodents, and as mentioned above, rimcazole attenuates cocaine-induced stimulation of locomotor activity. We recently have demonstrated that rimcazole and selected analogues bind the DAT in a conformation that differs from that for cocaine, which may be related to its lack of cocaine-like in vivo effects. However, the role of -receptors in the behavioral effects of these compounds remains to be established. In earlier studies of rimcazole analogues, we identified compounds with varying affinities and selectivities for -receptors and the DAT as potential in vivo probes. One series of rimcazole analogs was synthesized and tested for binding at -receptors and the DAT, as well as the serotonin (SERT) and norepinephrine (NET) transporters to investigate enantioselectivity and then make ester analogues of the eutomer. Most of these novel compounds demonstrated high affinity and selectivity for the DAT among the monoamine transporters. Most of the analogues showed comparable binding affinities at both DAT and -receptors with a maximal 16-fold DAT/-receptor selectivity. The SAR of these compounds will be exploited to synthesize compounds with greater selectivity for the -receptor over DAT as well as the DAT over -receptors in order to test the hypothesis that the unique actions of rimcazole are due to its dual and DAT actions, and to determine the optimal ratio of these effects.

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Reith, Maarten E A; Blough, Bruce E; Hong, Weimin C et al. (2015) Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter. Drug Alcohol Depend 147:1-19
Hiranita, Takato; Kohut, Stephen J; Soto, Paul L et al. (2014) Preclinical efficacy of N-substituted benztropine analogs as antagonists of methamphetamine self-administration in rats. J Pharmacol Exp Ther 348:174-91
Hiranita, Takato; Wilkinson, Derek S; Hong, Weimin C et al. (2014) 2-isoxazol-3-phenyltropane derivatives of cocaine: molecular and atypical system effects at the dopamine transporter. J Pharmacol Exp Ther 349:297-309
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