2-[4-(3,4-Dimethylphenyl)piperazin-1-ylmethyl]-1H benzoimidazole (A-381393), a selective dopamine D4 receptor antagonist

  title={2-[4-(3,4-Dimethylphenyl)piperazin-1-ylmethyl]-1H benzoimidazole (A-381393), a selective dopamine D4 receptor antagonist},
  author={Masaki Nakane and Marlon D. Cowart and Gin C. Hsieh and Loan N. Miller and Marie E. Uchic and Renjie Chang and Marc A Terranova and D L Donnelly-roberts and Marian T. Namovic and Thomas R. Miller and Jill M. Wetter and Kennan Marsh and Andrew O. Stewart and Jorge D. Brioni and Robert B. Moreland},

Evaluation of 18F-labeled benzodioxine piperazine-based dopamine D4 receptor ligands: lipophilicity as a determinate of nonspecific binding.

D4 radioligand 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-((6-fluoropyridin-3-yl)methyl)piperazine ([18F]3d), which revealed an excellent binding pattern with a high selectivity and limited nonspecific binding in vitro, and exhibited a high stability and an extremely high brain uptake in vivo.

L-745,870 Reduces l-DOPA-Induced Dyskinesia in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Lesioned Macaque Model of Parkinson's Disease

The data suggest that selective D4 receptor antagonists represent a potential therapeutic approach for l-DOPA-induced dyskinesia in PD, and it is noteworthy that l-745,870 has already undergone significant clinical development, has an excellent profile for a therapeutic candidate, and could be advanced rapidly to phase IIa clinical studies for dyskinexia in PD.

A-412997, a selective dopamine D4 agonist, improves cognitive performance in rats

WAY-100635 is a potent dopamine D4 receptor agonist

This study demonstrates that WAY-100635 is not a “selective” 5-HT1A receptor antagonist, as previously reported, and conclusions drawn from studies that employed this compound as a selective 5- HT1A antagonist may need to be reevaluated.

Dopamine D4 receptor involvement in the discriminative stimulus effects in rats of LSD, but not the phenethylamine hallucinogen DOI

Dopamine D4 receptor activation plays a significant modulatory role in the discriminative stimulus effects in LSD-90-trained rats, most markedly for the later temporal phase of LSD, but has no effect on the cue produced by DOI.

L-745,870 reduces the expression of abnormal involuntary movements in the 6-OHDA-lesioned rat.

The data suggest that L-745,870 may have a narrow therapeutic window as an antidyskinetic agent in advanced Parkinson's disease and reduces L-DOPA antiparkinsonian benefit in the rat model.

Dopamine Receptor Subtype-Selective Drugs: D2-Like Receptors

The most interesting structural features required for high selectivity and affinity are presented as well as structure–activity relationship (SAR) studies and the use of subtype-selective radioligands is discussed.

WAY 100635 produces discriminative stimulus effects in rats mediated by dopamine D4 receptor activation

The results indicate that the discriminative stimulus effect produced by WAY 100635 is mediated by activation of dopamine D4 receptors.



Biological profile of L-745,870, a selective antagonist with high affinity for the dopamine D4 receptor.

Results show that dopamine D4 receptor antagonism in the brain does not result in the same neurochemical consequences (increased dopamine metabolism or hyperprolactinemia) observed with typical neuroleptics.

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.

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

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.

These studies indicate that for some binding orientations, the phenylpiperazine moiety also plays a key role in determining efficacy, and 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.

Synthesis and structure-activity studies on N-[5-(1H-imidazol-4-yl)-5,6,7,8-tetrahydro-1-naphthalenyl]methanesulfonamide, an imidazole-containing alpha(1A)-adrenoceptor agonist.

Many of the compounds that were highly selective in vitro for the alpha(1A)-AR subtype were also more uroselective in vivo for increasing IUP over MAP than the nonselectivealpha(1)-agonists phenylpropanolamine (PPA) and ST-1059 (2, the active metabolite of midodrine), supporting the hypothesis that greater alpha( 1A) selectivity would reduce cardiovascular side effects.

L-745,870, a subtype selective dopamine D4 receptor antagonist, does not exhibit a neuroleptic-like profile in rodent behavioral tests.

D dopamine D4 receptor antagonism is not responsible for the ability of clozapine to attenuate amphetamine-induced hyperactivity and conditioned avoidance responding in rodents and the lack of effect of L-745,870 in these behavioral tests is consistent with the inability of the compound to alleviate psychotic symptoms in humans.

The agonist activities of the putative antipsychotic agents, L‐745,870 and U‐101958 in HEK293 cells expressing the human dopamine D4.4 receptor

Results show that the putative dopamine D 4 receptor antagonists, L‐745,870 and U‐101958 are not devoid of intrinsic activity at human recombinant dopamine D4.4 receptors and may not represent the most appropriate drugs for testing the benefit of D4 receptor antagonism in schizophrenic patients, if agonism should translate in vivo.

Receptor density as a factor governing the efficacy of the dopamine D4 receptor ligands, L‐745,870 and U‐101958 at human recombinant D4.4 receptors expressed in CHO cells

The results show that U‐101958 and L‐745,870 are partial agonists at human dopamine D4.4 receptors expressed in CHO cells, and their efficacy is governed by receptor density.