3-propoxy-beta-carboline and Disease-Models--Animal

To gain access to 3-propoxy-β-carboline hydrochloride (3-PBC·HCl) (1·HCl) and β-carboline-3-carboxylate-tert-butyl ester (βCCt) (2), potential clinical agents active against alcohol self-administration, a two-step route was developed. This process involves a palladium-catalyzed Buchwald-Hartwig coupling and an intramolecular Heck reaction. This two-step route provides rapid access to multigram quantities of 3-PBC (1) and βCCt (2), as well as analogues for studies of alcohol self-administration. The overall yield of 3-PBC (1) was improved from 8% to 50% by this route.

Topics: Alcoholism; Animals; Carbolines; Catalysis; Disease Models, Animal; Drug Design; Palladium; Primates; Rats; Self Administration

We investigated the potential role of the alpha1-containing GABA(A) receptor in regulating the reinforcing properties of alcohol. To accomplish this, we developed 3-propoxy-beta-carboline hydrochloride (3-PBC), a mixed agonist-antagonist benzodiazepine site ligand with binding selectivity at the alpha1 receptor. We then tested the capacity of 3-PBC to block alcohol-maintained responding in the ventral pallidum (VP), a novel alcohol reward substrate, which primarily expresses the alpha1-receptor isoform. Our results demonstrated that bilateral microinfusion of 3-PBC (0.5-40 microg) in the anterior and medial VP produced marked reductions in alcohol-maintained responding in a genetically selected rodent model of alcohol drinking. The VP infusions showed both neuroanatomical and reinforcer specificity because no effects were seen in sites dorsal to the VP (e.g., nucleus accumbens, caudate putamen). The saccharin-maintained responding was reduced only with the highest dose (40 microg). Parenteral injections of 3-PBC (1-20 mg/kg) also showed a similar selectivity on alcohol-maintained responding. Complementary in vitro studies revealed that 3-PBC exhibited a low partial agonist efficacy profile at recombinant diazepam-sensitive receptors (e.g., alpha1beta3gamma2, alpha2beta3gamma, and alpha3beta3gamma2). The selective suppression of 3-PBC on alcohol-maintained responding after central and parenteral administrations, together with its low-efficacy agonist profile, suggest that the reduction in alcohol-maintained behaviors was not attributable to a general suppression on consummatory behaviors. These results demonstrate that the alpha1-containing GABA(A) receptors in both the anterior and medial VP are important in regulating the reinforcing properties of alcohol. These receptors represent novel targets in the design and development of pharmacotherapies for alcohol-dependent subjects.

Topics: Alcoholism; Animals; Appetitive Behavior; Behavior, Animal; Benzodiazepines; Binding, Competitive; Carbolines; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Routes; Ethanol; GABA Antagonists; GABA Modulators; Globus Pallidus; Ligands; Male; Microinjections; Oocytes; Patch-Clamp Techniques; Protein Isoforms; Protein Subunits; Rats; Rats, Inbred Strains; Receptors, GABA-A; Recombinant Proteins; Reinforcement, Psychology; RNA, Complementary; Synaptosomes; Xenopus laevis