ABT 724 trihydrochloride

ABT 724 trihydrochloride is a highly selective D4 dopamine agonist [1][2], with an EC50 of 281 nM in increasing the binding activity of GTPγS in CHO cells transfected with human D4 receptors, and of 12.4 nM in increasing Ca2+ influx of HEK-293 cells co-transfected with a G protein (Gαq05) and rat/human D4 receptors [3].

The neurotransmitter dopamine (DA) is important for regulating functions of human T cell. Through D1/D5, D2, and D3 receptors, DA can activate resting T cells by stimulating the expression of surface integrins and the release of cytokines. By down-regulating nonreceptor tyrosine kinases, DA can inhibit the proliferation of activated T cells. Stimulation of dopamine D4 receptors can induce T cell quiescence [1].

With the presence of the D4 receptors, T cells were treated with the specific D4 DA agonist PD 168,077 at a concentration of 1 ?M at the onset of 48 h of TCR stimulation with anti-CD3/CD28 so that the D4 DA agonist remained throughout this period, The proliferation of these cells was significantly inhibited. This result was from the evidence of [3H]thymidine incorporation. When treated with another D4 DA agonist, ABT 724 trihydrochloride at a concentration of 1 ?M, T cells also showed similar results [1].

Clozapine has high affinity for the dopamine D4 receptor [4]. Compared to treatment with clozapine alone, clozapine plus 50 ?M or 25 ?M ABT-724 significantly increase the locomotor activity of zebrafish larvae. The effect of ABT-724 to protect larvae from the clozapine-induced hypoactivity is in a dose-dependent fashion [5].

References:
[1].  Sarkar C, Das S, Chakroborty D, et al. Cutting Edge: Stimulation of dopamine D4 receptors induce T cell quiescence by up-regulating Kruppel-like factor-2 expression through inhibition of ERK1/ERK2 phosphorylation. J Immunol, 2006, 177(11):7525-9.
[2].  Melis MR, Succu S, Mascia MS, et al. PD-168077, a selective dopamine D4 receptor agonist, induces penile erection when injected into the paraventricular nucleus of male rats. Neurosci Lett, 2005, 379(1):59-62.
[3].  Sanna F, Contini A, Melis MR, et al. Role of dopamine D4 receptors in copulatory behavior: Studies with selective D4 agonists and antagonists in male rats. Pharmacol Biochem Behav, 2015, 137:110-8.
[4].  Arranz M, Collier D, Sodhi M, et al. Association between clozapine response and allelic variation in 5-HT2A receptor gene. Lancet, 1995, 346(8970):281-2.
[5].  Boehmler W, Carr T, Thisse C, et al. D4 Dopamine receptor genes of zebrafish and effects of the antipsychotic clozapine on larval swimming behaviour. Genes Brain Behav, 2007, 6(2):155-66.

Discovery of 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole (ABT-724), a dopaminergic agent with a novel mode of action for the potential treatment of erectile dysfunction.[Pubmed:15239663]

J Med Chem. 2004 Jul 15;47(15):3853-64.

A new class of agents with potential utility for the treatment of erectile dysfunction has been discovered, guided by the hypothesis that selective D4 agonists are erectogenic but devoid of the side effects typically associated with dopaminergic agents. The lead agent 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole (1, ABT-724) was discovered by optimization of a series of benzimidazole arylpiperazines. This highly selective D4 agonist was found to be very potent and efficacious in vivo, eliciting penile erections in rats at a dose of 0.03 micromol/kg, with a positive response rate of 77% erectile incidence. Even at high doses, it was devoid of side effects in animal models of central nervous system behaviors, emesis, or nausea. The structure-activity relationship of the parent benzimidazole series leading to 1 is described, with the detailed in vitro and in vivo profiles described. Distinctive structural features were discovered that are associated with D4 selective agonism in this series of analogues.

Dopamine D4 ligands and models of receptor activation: 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole and related heteroarylmethylarylpiperazines exhibit a substituent effect responsible for additional efficacy tuning.[Pubmed:15084133]

J Med Chem. 2004 Apr 22;47(9):2348-55.

A series of subtype selective dopamine D(4) receptor ligands from the hetroarylmethylphenylpiperazine class have been discovered that exhibit a remarkable structure-activity relationship (SAR), revealing a substituent effect in which regiosubstitution on the terminal arylpiperazine ring can modulate functional or intrinsic activity. Other structure-dependent efficacy studies in the dopamine D(4) field have suggested a critical interaction of the heteroarylmethyl moiety with specific protein microdomains in controlling intrinsic activity. Our studies indicate that for some binding orientations, the phenylpiperazine moiety also plays a key role in determining efficacy. These data also implicate a kinetic or efficiency term, contained within measured functional affinities for agonists, which support a sequential binding and conformational stabilization model for receptor activation. The structural similarity between partial agonist and antagonist, within this subset of ligands, and lack of bioisosterism for this substituent effect are key phenomena for these hypotheses.

ABT-724 trihydrochloride is a potent and highly selective dopamine D4 receptor agonist with an EC50 of 12.4 nM for human dopamine D4 receptor. ABT-724 trihydrochloride is a potent partial agonist at the rat D4 (EC50 of 14.3 nM) and the ferret D4 receptor (EC50 of 23.2 nM), and has no effect on dopamine D1, D2, D3, or D5 receptors. ABT-724 trihydrochloride could be useful for the treatment of erectile dysfunction and has favorable side-effect profile.

ABT 724 trihydrochloride,587870-77-7,Natural Products,Dopamine Receptor, buy ABT 724 trihydrochloride , ABT 724 trihydrochloride supplier , purchase ABT 724 trihydrochloride , ABT 724 trihydrochloride cost , ABT 724 trihydrochloride manufacturer , order ABT 724 trihydrochloride , high purity ABT 724 trihydrochloride