Discovery of 2-(4-Pyridin-2-ylpiperazin-1-ylmethyl)-1<i>H</i>-benzimidazole (ABT-724), a Dopaminergic Agent with a Novel Mode of Action for the Potential Treatment of Erectile Dysfunction

Cowart, Marlon; Latshaw, Steven P.; Bhatia, Pramila; Daanen, Jerome F.; Rohde, Jeffrey J.; Nelson, Sherry L.; Patel, Meena; Kolasa, Teodozyj; Nakane, Masaki; Uchic, Marie E.; Miller, Loan; Terranova, Marc A.; Chang, Ruidong; Donnelly‐Roberts, Diana L.; Namovic, Marian T.; Hollingsworth, Peter R.; Martino, Brenda; Lynch, James J.; Sullivan, James P.; Hsieh, Gin C.; Moreland, Robert B.; Brioni, Jorge D.; Stewart, Andrew O.

doi:10.1021/jm030505a

Cited by 58 publications

(24 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, the functional properties of L750,667, PNU101,387G, ABT-724, and Ro10-5824 for the mutant receptors were the same as for the wild-type receptors: they were all antagonists because they did not activate the receptors and prevented activation by the agonist (Ϫ)-quinpirole. Two of the D4-selective ligands used in this study, ABT-724 and Ro10-5824, have been reported to possess partial agonist properties when using either [ 35 S]GTP␥S binding or FLIPR assays as functional end points (Powell et al, 2003;Cowart et al, 2004;Newman-Tancredi et al, 2008). However, using intracellular cAMP accumulation as a functional endpoint we found that ABT-724 and Ro10-5824 lacked agonist properties, but antagonized (Ϫ)-quinpirole activation in wild-type and mutant receptors.…”

Section: Resultsmentioning

confidence: 60%

Transmembrane Segment Five Serines of the D4 Dopamine Receptor Uniquely Influence the Interactions of Dopamine, Norepinephrine, and Ro10-4548

Cummings

Ericksen²,

Goetz³

et al. 2010

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Conserved serines of transmembrane segment (TM) five (TM5) are critical for the interactions of endogenous catecholamines with ␣ 1 -and ␣ 2 -adrenergic, ␤ 2 -adrenergic, and D1, D2, and D3 dopamine receptors. The unique high-affinity interaction of the D4 dopamine receptor subtype with both norepinephrine and dopamine, and the fact that TM5 serine interactions have never been studied for this receptor subtype, led us to investigate the interactions of ligands with D4 receptor TM5 serines. Serine-to-alanine mutations at positions 5.42 and 5.46 drastically decreased affinities of dopamine and norepinephrine for the D4 receptor. The D4-S5.43A receptor mutant had substantially reduced affinity for norepinephrine, but a modest loss of affinity for dopamine. In functional assays of cAMP accumulation, norephinephrine was unable to activate any of the mutant receptors, even though the agonist quinpirole displayed wild-type functional properties for all of them. Dopamine was unable to activate the S5.46A mutant and had reduced potency for the S5.43A mutant and reduced potency and efficacy for the S5.42A mutant. In contrast, Ro10-4548 [RAC-2Ј-2-hydroxy-3-4-(4-hydroxy-2-methoxyphenyl)-1-piperazinyl-propoxy-acetanilide], a catechol-like antagonist of the wild-type receptor unexpectedly functions as an agonist of the S5.43A mutant. Other noncatechol ligands had similar properties for mutant and wild-type receptors. This is the first example of a dopamine receptor point mutation selectively changing the receptor's interaction with a specific antagonist to that of an agonist, and together with other data, provides evidence, supported by molecular modeling, that catecholamine-type agonism is induced by different ligand-specific configurations of intermolecular H-bonds with the TM5 conserved serines.The D4 dopamine receptor has had a checkered history of popularity. It was for a time believed to be the ideal target for an atypical antipsychotic drug (for review see Schetz and Sibley, 2007;Schetz, 2009). The D4 receptor has also been pursued as a drug target for treating attention-deficit hyperactivity disorder (ADHD) and erectile dysfunction, but these possibilities remain controversial. A D4 polymorphic variant (D4.7) was reported to be hyporesponsive to dopamine and associated with a higher risk for ADHD (LaHoste et al., 1996). However, the relevance of a low-magnitude hyporesponsiveness is unclear, and the association of the D4.7 polymorphic variant has not always been replicated by different laboratories (for a review see Schetz and Sibley, 2007) with some studies even suggest-

show abstract

Section: Resultsmentioning

confidence: 60%

Transmembrane Segment Five Serines of the D4 Dopamine Receptor Uniquely Influence the Interactions of Dopamine, Norepinephrine, and Ro10-4548

Cummings

Ericksen²,

Goetz³

et al. 2010

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…In vivo administration to rats to test potential treatment of erectile dysfunction [184,185] WAY 100635 16.4 D4 receptor agonist and 5HT1A antagonist; produces discriminative stimulus effects in rats [186,187] PD 168077 8.7 Selective D4 agonist, proerectile effect in rats [188]; tested in mice for memory consolidation studies [189] PNU 96415E 3 Tested for antipsychotic potential [190] Ro 10-5824 5.2 Selective D4 agonist, increases novel exploration in mice [191] NGD 94-1 3…”

Section: Dopamine-related Diseasesmentioning

confidence: 99%

The dopamine D4 receptor: biochemical and signalling properties

Rondou

Haegeman

Craenenbroeck

2010

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

Dopamine is an important neurotransmitter that regulates several key functions in the brain, such as motor output, motivation and reward, learning and memory, and endocrine regulation. Dopamine does not mediate fast synaptic transmission, but rather modulates it by triggering slow-acting effects through the activation of dopamine receptors, which belong to the G-protein-coupled receptor superfamily. Besides activating different effectors through G-protein coupling, dopamine receptors also signal through interaction with a variety of proteins, collectively termed dopamine receptor-interacting proteins. We focus on the dopamine D4 receptor, which contains an important polymorphism in its third intracellular loop. This polymorphism has been the subject of numerous studies investigating links with several brain disorders, such as attention-deficit hyperactivity disorder and schizophrenia. We provide an overview of the structure, signalling properties and regulation of dopamine D4 receptors, and briefly discuss their physiological and pathophysiological role in the brain.

show abstract

“…ABT-724 is a selective dopamine D4 receptor agonist, which successfully induced penile erection in a rat model without side effects such as nausea and emesis (13). ABT-670 is known to have better oral bioavailability than ABT-724 while having similar efficacy (14).…”

Section: Clinical Trials To Develop Ed Therapeutics Targeting Alternamentioning

confidence: 99%

Research in pharmacotherapy for erectile dysfunction

Ryu¹,

Suh²,

Burnett³

2017

Transl. Androl. Urol.

View full text Add to dashboard Cite

Although oral phosphodiesterase-5 (PDE5) inhibitors are generally accepted as an effective therapy for erectile dysfunction (ED), men with ED from diabetes or radical prostatectomy respond poorly to these drugs. Many researchers have tried to develop novel therapeutics that target alternative molecular pathways. A group of therapeutics belongs to centrally acting agents that target dopamine and melanocortin receptors. The other one is the peripherally acting agents that target soluble guanylate cyclase, Rho-kinase pathway, and Maxi-K channel, etc. Also, a variety of preclinical studies by the application of biotherapies in the concept of therapeutic angiogenesis or neural regeneration as well as anti-fibrosis to regenerate damaged erectile tissue have been reported. This article will address the current therapeutic targets for ED under clinical or preclinical development, including pharmacotherapy and biotherapy which comprises protein therapy and gene therapy. In spite of numerous clinical trials that target alternative pathways, these agents have yet to reach the market. The results from preclinical studies targeting therapeutic angiogenesis, neural regeneration, and anti-fibrosis are promising.

show abstract

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

Cited by 58 publications

References 29 publications

Transmembrane Segment Five Serines of the D4 Dopamine Receptor Uniquely Influence the Interactions of Dopamine, Norepinephrine, and Ro10-4548

Transmembrane Segment Five Serines of the D4 Dopamine Receptor Uniquely Influence the Interactions of Dopamine, Norepinephrine, and Ro10-4548

The dopamine D4 receptor: biochemical and signalling properties

Research in pharmacotherapy for erectile dysfunction

Contact Info

Product

Resources

About