The design and synthesis of novel ligands with high affinities and selectivities for targeted receptors is imperative for the elucidation of the role of these systems in drug abuse. The receptors that have been targeted in this work are the dopamine transporter, the dopamine D1 receptor subtype and PCP sites on the N-Methyl-D-Aspartate (NMDA) receptor complex. 3a-Diphenylmethoxy tropane analogs, based on the dopamine uptake inhibitor, benztropine, have been prepared as novel probes for the dopamine transporter. Substitutions at the 3-position and at the nitrogen on the tropane ring have yielded very interesting series of compounds that demonstrate 1) high affinity binding at the dopamine transporter, 2) potent inhibition of dopamine uptake that is well correlated with binding affinities at the transporter, 3) >100-fold selectivities over the other monoamine transporters, 4) significantly lower binding affinities at muscarinic receptors than the parent drug and 5) behavioral profiles that are not cocaine-like. Structure-activity relationship studies reveal that these tropane analogs do not appear to be interacting at the same binding domain as cocaine and its congeners. Since these compounds are neither efficacious locomotor stimulants nor are they recognized by rats trained to discriminate cocaine from saline as being cocaine-like, they provide unique tools for which to study the dopamine transporter and its relationship to the reinforcing effects of cocaine. Further, these compounds may have therapeutic potential for cocaine abuse since they have a neurochemical profile that is similar to cocaine and yet they do not appear to have the reinforcing effects that are associated with psychomotor stimulants. A novel series of N-alkylamino-benzazepines have been prepared that are dopamine D1 antagonists. These compounds have provided new insight into the dopamine D1 receptor pharmacophore as well as providing a template for future peripherally active dopamine D1 antagonists. It is anticipated that these compounds will serve as the first peripheral dopamine D1 receptor antagonists that will provide insight into the role of these receptors in cocaine toxicity. Morphinan analogs based on dextromethorphan have been synthesized that demonstrate potent and efficacious anticonvulsant and neuroprotectant actions in animal models. The anticonvulsant actions of these compounds is well correlated with binding affinities of these compounds at PCP sites on the NMDA receptor complex. These compounds are low affinity uncompetitive antagonists and do not possess a PCP-like behavioral profile. Hence, they may have clinical utility in treating seizure disorders, including cocaine-induced seizures. In addition, the relationship between NMDA receptors and the pharmacology of cocaine may be further characterized using this novel series of compounds.
