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Five groups of previously synthesized and initially screened non-substituted and 4-halogenated arylpiperazin-1-yl-ethyl-benzimidazoles were estimated for their in-vitro binding affinities at the rat D-2, 5-HT2A, and alpha(1)-adrenergic receptors. Among all these compounds, 2-methoxyphenyl and 2-chlorophenyl piperazines demonstrate the highest affinities for the tested receptors. The effects of 4-halogenation of benzimidazoles reveal that substitution with brominemay greatly increase the affinity of the compounds for the studied receptors, while the effect of substitution with chlorine is less remarkable. Most of the tested components show 5-HT2A/D-2 pK(i) binding ratios slightly above or less than 1, while only 4-chloro-6-(2-{4-[3-(trifluoromethyl) phenyl]piperazin-1-yl}ethyl)-1H-benzimidazole expresses an appropriate higher binding ratio (1.14), which was indicated for atypical neuroleptics. This compound exhibits a non-cataleptic action in rats and prevents d-amphetamine-induced hyperlocomotion in mice, which suggest its atypical antipsychotic potency.

Five groups of previously synthesized and initially screened non-substituted and 4-halogenated arylpiperazin-1-yl-ethyl-benzimidazoles were estimated for their in-vitro binding affinities at the rat D2, 5-HT2A, and alpha(1)-adrenergic receptors. Among all these compounds, 2-methoxyphenyl and 2-chlorophenyl piperazines demonstrate the highest affinities for the tested receptors. The effects of 4-halogenation of benzimidazoles reveal that substitution with brominemay greatly increase the affinity of the compounds for the studied receptors, while the effect of substitution with chlorine is less remarkable. Most of the tested components show 5-HT2A/D2 pK(i) binding ratios slightly above or less than 1, while only 4-chloro-6-(2-{4-[3-(trifluoromethyl) phenyl]piperazin-1-yl}ethyl)-1H-benzimidazole expresses an appropriate higher binding ratio (1.14), which was indicated for atypical neuroleptics. This compound exhibits a non-cataleptic action in rats and prevents d-amphetamine-induced hyperlocomotion in mice, which suggest its atypical antipsychotic potency.

Six newly synthesized heterocyclic (2-nitrophenyl)piperazines, with a specific structure of the heteroaryl group, whichmimics the catechol moiety of dopamine (benzimidazoles and substituted benzimidazoles), were evaluated for their binding affinity to rat dopamine (DA), serotonin (5-HT) and _1 receptors. All compounds with a benzimidazole group had a 5-HT2A/D2 receptors binding ratio characteristic for atypical neuroleptics (>1, pK i values). Compound 7c, 4-bromo-6-{2-_4-(2-nitrophenyl)piperazin- 1-yl_ethyl}-1H-benzimidazole, expressed higher affinities for all receptor classes than clozapine. Also, it exhibited the best characteristic for atypical neuroleptics and presents a compound with the best profile for further in vivo investigations., Sintetisano je šest heterocikličnih (2-nitrofenil)piperazina sa specifičnom heteroaril grupom, koja podražava kateholsku grupu dopamina (benzimidazoli i supstituisani benzimidazoli), i ispitan je njihov afinitet ka dopaminskim, serotoninskim i _1 receptorima. Sva jedinjenja sa benzimidazolskim grupama su pokazala 5-HT 1A/D2 odnos vezivanja karakterističan za atipične neuroleptike (>1, pK i vrednosti). Jedinjenje 7c, 4-bromo-6-{2-_4-(2-nitrofenil)piperazin-1-il_etil}-1H-benzimidazol, pokazalo je izraženiji afinitet ka svim klasama receptora u poređenju sa klozapinom i takođe predstavlja jedinjenje sa najboljim karakteristikama za dalja in vivo istraživanja.

Six newly synthesized heterocyclic (2-nitroplienyl)piperazines. with a specific structure of the heteroaryl group, which mimics the catechol moiety of dopamine (benzimidazoles and substituted benzimidazoles), were evaluated for their binding affinity to rat dopamine (DA), serotonin (5-HT) and alpha I receptors. All compounds with a benzimidazole group had a 5-HT2A/D-2 receptors binding ratio characteristic for atypical neuroleptics ( gt 1, pK(i) values). Compound 7e, 4-bromo-6-{2-[4-(2-nitrophenyl)piperazin-1-yl]etliyl}-1H-benziniidazole, expressed higher affinities for all receptor classes than clozapine. Also, it exhibited the best characteristic for atypical neuroleptics and presents a compound with the best profile for further in vivo investigations., Sintetisano je šest heterocikličnih (2-nitrofenil)piperazina sa specifičnom heteroaril grupom, koja podražava kateholsku grupu dopamina (benzimidazoli i supstituisani benzimidazoli), i ispitan je njihov afinitet ka dopaminskim, serotoninskim i _1 receptorima. Sva jedinjenja sa benzimidazolskim grupama su pokazala 5-HT 1A/D2 odnos vezivanja karakterističan za atipične neuroleptike ( gt 1, pK i vrednosti). Jedinjenje 7c, 4-bromo-6-{2-_4-(2-nitrofenil)piperazin-1-il_etil}-1H-benzimidazol, pokazalo je izraženiji afinitet ka svim klasama receptora u poređenju sa klozapinom i takođe predstavlja jedinjenje sa najboljim karakteristikama za dalja in vivo istraživanja.

The docking of several 1-benzyl-4-arylpiperazines to the dopamine receptor (DAR) D 2 was examined. The results demonstrated that the interaction of protonated N1 of the piperazine ring with Asp 86 (III.32) and edge-to-face interactions of the aromatic ring of the arylpiperazine part of the ligand with Phe 178 (VI.44), Trp 182 (VI.48) and Tyr 216 (VII.58) of the receptor, represent the major stabilizing forces. Besides, the hydrogen bond acceptor group in position 2 of the phenylpiperazine aromatic ring could build one more hydrogen bond with Trp 182 (VI.48). Bulky substituents in position 4 were not tolerated due to the unfavorable sterical interaction with Phe 178 (VI.44). Substituents in position 2 and 3 were found to be sterically well tolerated. Introduction of electron attractive -NO 2 group in position 3 of arylpiperazines decreased, while electron donors (-OMe) and the second aromatic ring (naphthyl) increased the binding affinity comparing to that of the phenylpiperazine 1. This can be explained in terms of favoured edge-to-face interactions in ligands with a high negative electrostatic surface potential (ESP) in the centre of aromatic residue of arylpiperazines. Thus, besides the salt bridges and hydrogen bonds, edge-to-face interactions significantly contribute to arylpiperazine ligands to form complexes with the DAR D 2 . Phe 178 (VI.44), Trp 182 (VI.48) and Tyr 216 (VII.58) can be considered as a part of the ancillary DAR D 2 pocket preserved in most G protein-coupled receptors of the A class and obviously, the arylpiperazine structural motif represents one of the privileged structures that bind to this pocket., Die Bindung von mehreren 1-Benzyl-4-arylpiperazin-Derivaten an den Dop-amin D2-Rezeptor wurde untersucht. Die Ergebnisse zeigen, daß die Interaktion des protonierten N1 des Piperazin-Rings mit Asp 86 (III.32) und „Edge-to-Face”-Interaktionen des aromatischen Rings des Acrylpiperazin-Anteils mit Phe 178 (VI.44), Trp 182 (VI.48) und Tyr 216 (VII.58) des Rezeptors die größte stabilisierende Kraft darstellt. Neben der Wasserstoffbrücken-Akzeptorgruppe in Position 2 von Phenylpiperazin kann der aromatische Ring eine zusätzliche Wasserstoffbrücke mit Trp 182 bilden. Große Substituenten in Position 4 wurden aufgrund sterischer Interaktionen mit Phe 179 (VI.44) nicht toleriert. Die Einführung der Elektronenakzeptorgruppe -NO2 in Position 3 von Arylpiperazin verminderte die Bindungsaffinität im Vergleich zu Phenylpiperazin 1, während die Elektronendonatorgruppe -OMe und der zweite aromatische Ring (Naphthyl) die Bindungsaffinität verstärkte. Dies kann mit einer bevorzugten „Edge-to-Face”-Interaktion bei Liganden mit stark negativem elektrostatischem Oberflächenpotential (ESP) im Zentrum des aromatischen Teils von Arylpiperazin erklärt werden. Neben Ionen- und Wasserstoffbrükken sind daher „Edge-to-Face”-Interaktionen maßgeblich mit an der Komplexbildung zwischen Arylpiperazin-Liganden und dem Dopamin D2-Rezeptor beteiligt. Phe 178 (VI.44), Trp 182 (VI.48) und Tyr 216 (VII.58) können als Teil einer zusätzlichen Dopamin D2-Rezeptortasche angesehen werden, die in den meisten GPRCs (G protein-coupled receptors) der AKlasse erhalten ist. Offensichtlich repräsentiert das Strukturmotiv von Arylpiperazin eine begünstigte Struktur, die an diese Tasche bindet.

5-[3-(4-Arylpiperazin-1-yl)propyl]-1H-benzimidazoles and 5-[2-(4-aryipiperazin-1-yl)ethoxy]-1H-benzimidazoles were synthesized and their affinity for the D-1, D-2 and 5-HT1A, receptors examined. They expressed a rather high affinity for the D-2 doparnine receptor. The main features of ligand-D-2 receptor interactions revealed by docking analyses were: salt bridge between piperazine ring protonated N-1 and Asp 86, hydrogen bonds of ligand bezimidazole part with Ser 141, Ser 122 and His 189, edge-to-face interactions of arylpiperazine aromatic ring with Phe 178, Tyr 216 and Trp 182 and hydrogen bond between ethereal oxygen in ethylenoxy ligands and hydrogen of Phe 185 or Trp 115. The most active 5-{2-[4-(2-methoxyphenyl)-piperazin-1-yl]ethoxy}-1,3-di hydro-2H-benzimidazole-2-thione (27) has a maximal number of attractive interactions. A satisfactory correlation between docking of the compounds into the D-2 receptor and competition binding results was observed.

Docking of several 1-{2-[5-(1H-benzimidazole-2-thione)]ethyl}-4- and 1-benzylarylpiperazines to the D 2 dopamine receptor (DAR) was examined. The binding pocket of the D 2 DAR defined according to Teeter and DuRand [1] was extended using the Insight II software. It was found that (i) the interaction of the protonated N1 of the piperazine ring with Asp86, (ii) the hydrogen bond formation between the benzimidazole part of the ligand and Ser141, as well as Ser122, and (iii) the edge-to-face interactions of the aromatic ring or arylpiperazine part of the ligand with Phe178, Tyr216 and Trp182 of the receptor represent the mayor stabilizing forces. Besides, the hydrogen bond acceptor group in position 2 of the phenylpiperazine aromatic ring could form one more hydrogen bond with Trp182. Bulky substituents in position 4 are not tolerated, due to the unfavorable sterical interaction with Phe178. Substituents in positions 2 and 3 are sterically well tolerated. Electron-attractive groups (F, Cl, CF 3 , and NO 2 ) decreased, while electron donors (-OMe) and the second aromatic ring (naphthyl) increased the binding affinity, as compared to that of the parent compound 1. This can be explained by strong edge-to-face interactions of negative electrostatic surface potential (ESP) in the center of aromatic residues of the ligand with positive-ESP protons in the aromatic residues of the receptor. Thus, besides the salt bridges and hydrogen bonds, edge-to-face interactions significantly contribute to arylpiperazine ligands forming complexes with the D 2 DAR.

Docking of several 1-{2-[5-(1H-benzimidazole-2-thione)]ethyl}-4- and 1-benzylarylpiperazines to the D-2 dopamine receptor (DAR) was examined. The binding pocket of the D-2 DAR defined according to Teeter and DuRand [1] was extended using the Insight II software. It was found that (i) the interaction of the protonated N1 of the piperazine ring with Asp86, (ii) the hydrogen bond formation between the benzimidazole part of the ligand and Ser141, as well as Ser122, and (iii) the edge-to-face interactions of the aromatic ring or arylpiperazine part of the ligand with Phe178, Tyr216 and Trpl 82 of the receptor represent the mayor stabilizing forces. Besides, the hydrogen bond acceptor group in position 2 of the phenylpiperazine aromatic ring could form one more hydrogen bond with Trp182. Bulky substituents in position 4 are not tolerated, due to the unfavorable sterical interaction with Phe178. Substituents in positions 2 and 3 are sterically well tolerated. Electron-attractive groups (F, Cl, CF3, and NO2) decreased, while electron donors (-OMe) and the second aromatic ring (naphthyl) increased the binding affinity, as compared to that of the parent compound 1. This can be explained by strong edge-to-face interactions of negative electrostatic surface potential (ESP) in the center of aromatic residues of the ligand with positive-ESP protons in the aromatic residues of the receptor. Thus, besides the salt bridges and hydrogen bonds, edge-to-face interactions significantly contribute to arylpiperazine ligands forming complexes with the D-2 DAR.