No abstract

Apomorphine, a nonselective dopamine receptor agonist, facilitates penile erection and is effective in patients suffering from erectile dysfunction. The specific dopamine receptor subtype(s) responsible for its erectogenic effect is not known. Here we report that the dopamine D4 receptor plays a role in the regulation of penile function. ABT-724 is a selective dopamine D 4 receptor agonist that activates human dopamine D 4 receptors with an EC50 of 12.4 nM and 61% efficacy, with no effect on dopamine D 1, D2, D3, or D5 receptors. ABT-724 dose-dependently facilitates penile erection when given s.c. to conscious rats, an effect that is blocked by haloperidol and clozapine but not by domperidone. A proerectile effect is observed after intracerebroventricular but not intrathecal administration, suggesting a supraspinal site of action. s.c. injections of ABT-724 increase intracavernosal pressure in awake freely moving rats. In the presence of sildenafil, a potentiation of the proerectile effect of ABT-724 is observed in conscious rats. The ability of ABT-724 to facilitate penile erection together with the favorable side-effect profile indicates that ABT-724 could be useful for the treatment of erectile dysfunction. P enile erection is the result of a complex series of integrated neuronal and vascular events that leads to accumulation of blood in the penis to achieve rigidity. The coordination of several neural events is required to release endogenous mediators (i.e., nitric oxide) at the level of the penile smooth muscle to induce relaxation, whereas a disruption of this series of events can lead to erectile dysfunction (ED) (1, 2). Traditionally, drugs used for the treatment of ED have had a peripheral site of action, including phosphodiesterase (PDE)-5 inhibitors like sildenafil, but the recent demonstration that apomorphine can facilitate penile erection in ED patients has introduced a new approach to treatment, because apomorphine acts on central dopaminergic systems (3,4). Dopamine is the main catecholamine in the CNS and is involved in a variety of physiological functions, including sexual behavior, cognition, motor coordination, cardiovascular control, reward, hormonal regulation; abnormalities in dopaminergic neurotransmission have been implicated in Parkinson's disease, schizophrenia, attention-deficit disorder, depression, and drug abuse, among other disorders (5, 6). The regional distribution of the receptor subtypes, the recent generation of knock-out animals, and the availability of a large number of dopaminergic agents have aided researchers in clarifying the biological role of the dopamine receptors. Dopamine receptors in mammalian tissues have been classified as D 1 -like (D 1 and D 5 ) and D 2 -like (D 2 , D 3 , and D 4 ) based on their binding properties and their ability to activate or inhibit forskolin-induced adenylate cyclase activity, a classification supported by the cloning of the different subtypes during the last decade (7,8).Within the D 2 -like family, the D 2 receptor is highly expressed...

High-throughput screening (HTS) identified benzothiazole analogue 3 as a potent fatty acid amide hydrolase (FAAH) inhibitor. Structure-activity relationship (SAR) studies indicated that the sulfonyl group, the piperidine ring and benzothiazole were the key components to their activity, with 16j being the most potent analogue in this series. Time-dependent preincubation study of compound 3 was consistent with it being a reversible inhibitor. Activity-based protein-profiling (ABPP) evaluation of 3 in rat tissues revealed that it had exceptional selectivity and no off-target activity with respect to other serine hydrolases. Molecular shape overlay of 3 with a known FAAH inhibitor indicated that these compounds might act as transition-state analogues, forming putative hydrogen bonds with catalytic residues and mimicking the charge distribution of the tetrahedral transition state. The modeling study also indicated that hydrophobic interactions of the benzothiazole ring with the enzyme contributed to its extraordinary potency. These compounds may provide useful tools for the study of FAAH and the endocannabinoid system.

SAR (structure-activity relationship) studies of triazafluorenone derivatives as potent mGluR1 antagonists are described. The triazafluorenone derivatives are non-amino acid derivatives and noncompetitive mGluR1 antagonists that bind at a putative allosteric recognition site located within the seven-transmembrane domain of the receptor. These triazafluorenone derivatives are potent, selective, and systemically active mGluR1 antagonists. Compound 1n, for example, was a very potent mGluR1 antagonist (IC50 = 3 nM) and demonstrated full efficacy in various in vivo animal pain models.