Interaction of arylpiperazine ligands with the hydrophobic part of the 5-HT1A receptor binding site

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.

Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Modelling Of 5-ht 1a Receptor Binding Sitementioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

See 2 more Smart Citations

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

“…Moreover, although the exceptionally high affinity of compound 5 is probably not due to its ability to form a hydrogen bond between a substituent and Asn-386 of the receptor (like the OCH 3 substituent), but rather solvent accessibility and hydrophobic interaction with the receptor are decisive. In fact, Zlatovic et al [24] have recently reported that some arylpiperazine, such as naphthylpiperazine, can interact directly with the hydrophobic part of the 5-HT 1A receptor binding site. In particular the hydrophobic part of the binding site in the 5-HT 1A receptor, formed by Trp 358, Phe 361, and Tyr 390, is significant for the stabilization of the ligand-receptor complex.…”

Section: Resultsmentioning

confidence: 97%

Synthesis and In‐vitro Pharmacological Evaluation of New 5‐HT_1AReceptor Ligands Containing a Benzotriazinone Nucleus

Fiorino

Severino

Angelis

et al. 2007

This paper reports the microwave-assisted synthesis and the binding assays on the 5-HT(1A), 5-HT(2A) and 5-HT(2C) receptors of new benzotriazinone derivatives, in order to identify selective ligands for the 5-HT(1A) subtype receptor. Conventional and microwave heating of the reactions were compared. Good yields and short reaction times are the main advantages of our synthetic route. More active compounds were selected and further evaluated for their binding affinities on D(1), D(2) dopaminergic and alpha(1), alpha(2) adrenergic receptors. The 3-(2-(4-(naphthalen-1-yl)piperazin-1-yl)ethyl)benzo[d][1,2,3]triazin-4(3H)-one 5 with K(i)= 0.000178 nM was the most active and selective derivative for the 5-HT(1A)receptor with respect to other serotonin receptors and the most selective derivative compared to dopaminergic and adrenergic receptors.

N‐{[2‐(4‐Phenyl‐piperazin‐1‐yl)‐ethyl]‐phenyl}‐arylamides with Dopamine D₂ and 5‐Hydroxytryptamine 5HT₁_A Activity: Synthesis, Testing, and Molecular Modeling

Šukalović

Bogdan

Tovilović

et al. 2013

The ratio of affinities toward the dopamine D₂ and the 5-hydroxytryptamine 5-HT(1A) receptors is one of the important parameters that determine the efficiency of antipsychotic drugs. Here, we present the synthesis of ortho-, meta-, and para-N-{[2-(4-phenyl-piperazin-1-yl)-ethyl]-phenyl}-arylamides and their structure-activity relationship studies on dopamine D₂ and 5-hydroxytryptamine 5-HT(1A) receptors. It was shown that the biological activity of the described ligands strongly depends on their topology as well as on the nature of the heteroaryl group in the head of the molecules. Docking simulations together with conformational analysis revealed a rational explanation for the ligands' behavior. The molecular model of receptor-ligand interactions described herein provided us with a tool for the rational design of new compounds with a favorable D₂/5-HT(1A) profile.