trans-1-[(2-Phenylcyclopropyl)methyl]-4-arylpiperazines:  Mixed Dopamine D2/D4 Receptor Antagonists as Potential Antipsychotic Agents

Zhang, Xiaoyan; Hodgetts, Kevin J.; Rachwał, Stanisław; Zhao, He; Wasley, Jan W. F.; Craven, Kimberly; Brodbeck, Robbin; Kieltyka, Andrzej; Hoffman, Diane C.; Bacolod, Maria D.; Girard, Brian J.; Tran, Jennifer; Thurkauf, Andrew

doi:10.1021/jm990562x

Cited by 42 publications

(27 citation statements)

References 26 publications

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“…In D 2 -, 5-HT 2A -, and a 1 -functional tests most of them behaves as antagonist [13,15,16] although few exceptions are reported in the literature [17]. The recently published trans-1-[(2-phenylcyclopropyl)methyl]-4-arylpiperazines [18] K i values represent the means of three independent experiments, done in triplicate using eight ligand concentrations (1.0 nM -0.1 mM), according to the methods described in Experimental (section 4); S.E.M. = standard error of mean; na = not applicable.…”

Section: Resultsmentioning

confidence: 99%

1‐Cinnamyl‐4‐(2‐methoxyphenyl)piperazines: Synthesis, Binding Properties, and Docking to Dopamine (D₂) and Serotonin (5‐HT_1A) Receptors

Penjišević

Šukalović

Andrić

et al. 2007

Archiv der Pharmazie

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Clinical properties of atypical antipsychotics are based on their interaction with D(2) dopamine receptor and serotonin 5-HT(1A) and 5-HT(2A) receptors. As a part of our research program on new antipsychotics, we synthesized various derivatives of 1-cinnamyl-4-(2-methoxyphenyl)piperazines, and evaluated their affinities for D(2), 5-HT(1A), 5-HT(2A), and adrenergic (alpha(1)) receptors using radioligand-binding assays. In addition, we performed docking analysis using models for the D(2) and 5-HT(1A) receptors. All compounds exhibited low to moderate affinity to 5-HT(1A) and 5-HT(2A) receptors, high affinity to the D(2 )receptor and large variability in affinities for the alpha(1) receptor. Docking analysis indicated that the binding to D(2) and 5-HT(1A) receptors is based on (i) interaction between protonated N1 of the piperazine ring and various aspartate residues, (ii) hydrogen bonds between various moieties of the ligand and the residues of threonine, serine, histidine or tryptophane, and (iii) edge-to-face interactions of the aromatic ring of the arylpiperazine moiety with phenylalanine or tyrosine residues. Docking data for the D(2) receptor can account for the binding properties obtained in binding assays, suggesting that the model is reliable and robust. However, docking data for the 5-HT(1A) receptor cannot account for actual binding properties, suggesting that further refinement of the model is required.

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Section: Resultsmentioning

confidence: 99%

1‐Cinnamyl‐4‐(2‐methoxyphenyl)piperazines: Synthesis, Binding Properties, and Docking to Dopamine (D₂) and Serotonin (5‐HT_1A) Receptors

Penjišević

Šukalović

Andrić

et al. 2007

Archiv der Pharmazie

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“…The choice of ( R )-phenylglycinol as the alcohol component was based on its successful use in the resolution of other racemic carboxylic acids and the ease of cleavage of the resulting diastereomers under acidic conditions that involves an N,O -acyl transfer. The carboxylic acids (+) -12a and (−) -12a , whose optical rotations were compared with the known compounds in the literature,51 were then converted individually to (+)-and (−)- trans -(2-phenylcyclopropyl)methylamine hydrochloride ((+) -14a and (−) -14a ) using the same method as described above 52…”

Section: Chemistrymentioning

confidence: 99%

Selective 5-Hydroxytryptamine 2C Receptor Agonists Derived from the Lead Compound Tranylcypromine: Identification of Drugs with Antidepressant-Like Action

et al. 2009

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We report here the design, synthesis, and pharmacological properties of a series of compounds related to tranylcypromine (9), which itself was discovered as a lead compound in a high-throughput screening campaign. Starting from 9, which shows modest activity as a 5-HT 2C agonist, a series of 1-aminomethyl-2-phenylcyclopropanes was investigated as 5-HT 2C agonists through iterative structural modifications. Key pharmacophore feature of this new class of ligands is a 2-aminomethyltrans-cyclopropyl side chain attached to a substituted benzene ring. Among the tested compounds, several were potent and efficacious 5-HT 2C receptor agonists with selectivity over both 5-HT 2A and 5-HT 2B receptors in functional assays. The most promising compound is 37 with 120-and 14-fold selectivity over 5-HT 2A and 5-HT 2B , respectively (EC 50 = 585, 65, and 4.8 nM at the 2A, 2B, and 2C subtypes, respectively). In animal studies, compound 37 (10-60 mg/kg) decreased immobility time in the mouse forced swim test.

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“…The neurobiological significance of enhancements in baseline PPI is not fully elucidated, but it does not seem specifically related to antipsychotic activity. In fact, while the ability of antipsychotic drugs to increase baseline PPI has been occasionally shown (Depoortere et al, 1997;Sipes and Geyer, 1997;Zhang et al, 2000), it has also been proposed to depend on experimental artifacts, since the bulk of evidence has denoted no such effect ). More interestingly, PPI enhancements might reflect an improvement in preattentional and executive functions.…”

Section: Intrinsic Effects Of Tpm On Prepulse Inhibitionmentioning

confidence: 99%

Effects of Topiramate on the Prepulse Inhibition of the Acoustic Startle in Rats

Frau

Orrù

Fà

et al. 2006

Neuropsychopharmacol

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The anticonvulsant topiramate (TPM) has been recently proposed as a novel adjuvant therapy for bipolar disorder and schizophrenia, yet its efficacy remains controversial. As both disorders are characterized by gating deficits, we tested the effects of TPM on the behavioral paradigm of prepulse inhibition (PPI) of the acoustic startle response, a validated animal model of sensorimotor gating. TPM (10, 18, 32, 58, 100 mg/kg, intraperitoneal, i.p.) enhanced PPI in rats in a dose-dependent fashion, prevented the PPI reduction mediated by the dopaminergic agonist apomorphine (0.25 mg/kg, subcutaneous, s.c.) and potentiated the effects of the antipsychotic drugs haloperidol (0.05, 0.1 mg/kg, i.p.) and clozapine (2.5, 5 mg/kg, i.p.). Conversely, TPM elicited no significant effect on the PPI disruption mediated by the NMDA receptor antagonist dizocilpine (0.05, 0.1 mg/kg, s.c.) and surprisingly antagonized the attenuation of dizocilpine-induced PPI disruption mediated by clozapine (5 mg/kg, i.p.). Our results suggest that TPM may exert diverse actions on the neural substrates of sensorimotor gating. While the pharmacological mechanisms of such effects are still elusive, our findings might contribute to shed light on some controversies on the therapeutic action of TPM, and point to this drug as a putative novel adjuvant therapy for some clusters of gating disturbances.

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trans-1-[(2-Phenylcyclopropyl)methyl]-4-arylpiperazines: Mixed Dopamine D₂/D₄ Receptor Antagonists as Potential Antipsychotic Agents

Cited by 42 publications

References 26 publications

1‐Cinnamyl‐4‐(2‐methoxyphenyl)piperazines: Synthesis, Binding Properties, and Docking to Dopamine (D₂) and Serotonin (5‐HT_1A) Receptors

1‐Cinnamyl‐4‐(2‐methoxyphenyl)piperazines: Synthesis, Binding Properties, and Docking to Dopamine (D₂) and Serotonin (5‐HT_1A) Receptors

Selective 5-Hydroxytryptamine 2C Receptor Agonists Derived from the Lead Compound Tranylcypromine: Identification of Drugs with Antidepressant-Like Action

Effects of Topiramate on the Prepulse Inhibition of the Acoustic Startle in Rats

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trans-1-[(2-Phenylcyclopropyl)methyl]-4-arylpiperazines: Mixed Dopamine D2/D4 Receptor Antagonists as Potential Antipsychotic Agents

Cited by 42 publications

References 26 publications

1‐Cinnamyl‐4‐(2‐methoxyphenyl)piperazines: Synthesis, Binding Properties, and Docking to Dopamine (D2) and Serotonin (5‐HT1A) Receptors

1‐Cinnamyl‐4‐(2‐methoxyphenyl)piperazines: Synthesis, Binding Properties, and Docking to Dopamine (D2) and Serotonin (5‐HT1A) Receptors

Selective 5-Hydroxytryptamine 2C Receptor Agonists Derived from the Lead Compound Tranylcypromine: Identification of Drugs with Antidepressant-Like Action

Effects of Topiramate on the Prepulse Inhibition of the Acoustic Startle in Rats

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Product

Resources

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trans-1-[(2-Phenylcyclopropyl)methyl]-4-arylpiperazines: Mixed Dopamine D₂/D₄ Receptor Antagonists as Potential Antipsychotic Agents

1‐Cinnamyl‐4‐(2‐methoxyphenyl)piperazines: Synthesis, Binding Properties, and Docking to Dopamine (D₂) and Serotonin (5‐HT_1A) Receptors

1‐Cinnamyl‐4‐(2‐methoxyphenyl)piperazines: Synthesis, Binding Properties, and Docking to Dopamine (D₂) and Serotonin (5‐HT_1A) Receptors