Synthesis, binding properties and receptor docking of 4-halo-6-[2-(4-arylpiperazin-1-yl)ethyl]-1H-benzimidazoles, mixed ligands of D2 and 5-HT1A receptors (original) (raw)
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European Journal of Medicinal Chemistry, 2005
Arylpiperazin-1-yl)propyl]-1H-benzimidazoles and 5-[2-(4-arylpiperazin-1-yl)ethoxy]-1H-benzimidazoles were synthesized and their affinity for the D 1 , D 2 and 5-HT 1A receptors examined. They expressed a rather high affinity for the D 2 dopamine 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-dihydro-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.
Journal of The Serbian Chemical Society, 2007
Eight new compounds with halogen atom introduced into the benzimidazole-2-thione dopaminergic pharmacophore of 5-[2-(4-arylpiperazin-1-yl)ethyl]-1,3-dihydro-2H-benzimidazole-2-thiones with the arylpiperazine part of the molecule being selected according to known structure-affinity requirements, have been synthesized. All the new compounds were evaluated for the in vitro binding affinity at the dopamine (DA) D 1 and D 2 and serotonin 5-HT 1A receptors by the competitive radioassays, performed on synaptosomal membranes prepared from fresh bovine caudate nuclei and hippocampi. All the new compounds were strong competitors for the binding of the radioligands to the D 2 and 5-HT 1A receptors, with the most active of them having 34 and 170 time higher affinity than non-halogenated congeners in the D 2 DA receptor radioassays (compounds 9.1b and 9.2b, respectively). Divergently, these compounds were without significant affinities for the D 1 DA receptors.
Molecules, 2012
A series of novel benzobthiophen-2-yl-3-(4-arylpiperazin-1-yl)-propan-1-one derivatives 6a-f, 7a-f and their corresponding alcohols 8a-f were synthesized and evaluated for their affinity towards 5-HT 1A receptors. The influence of arylpiperazine moiety and benzobthiophene ring substitutions on binding affinity was studied. The most promising analogue, 1-(benzo[b]thiophen-2-yl)-3-(4-(pyridin-2-yl)piperazin-1-yl)propan-1-one (7e) displayed micromolar affinity (K i = 2.30 μM) toward 5-HT 1A sites. Docking studies shed light on the relevant electrostatic interactions which could explain the observed affinity for this compound.
Bioorganic & Medicinal …, 2010
We described herein the design, synthesis, and pharmacological evaluation of N-phenylpiperazine heterocyclic derivatives as multi-target compounds potentially useful for the treatment of schizophrenia. The isosteric replacement of the heterocyclic ring at the biaryl motif generating pyrazole, 1,2,3-triazole, and 2-methylimidazole[1,2-a]pyridine derivatives resulted in 21 analogues with different substitutions at the para-biaryl and para-phenylpiperazine positions. Among the compounds prepared, 4 (LASSBio-579) and 10 (LASSBio-664) exhibited an adequate binding profile and a potential for schizophrenia positive symptoms treatment without cataleptogenic effects. Structural features of this molecular scaffold are discussed regarding binding affinity and selectivity for D 2-like, 5-HT 1A , and 5-HT 2A receptors.
Frontiers in Chemistry
Neurleptic drugs, e.g., aripiprazole, targeting the dopamine D 2S and D 3 receptors (D 2S R and D 3 R) in the central nervous system are widely used in the treatment of several psychotic and neurodegenerative diseases. Therefore, a new series of benzothiazole-based ligands (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) was synthesized by applying the bioisosteric approach derived from the selective D 3 Rs ligand BP-897 (1) and its structurally related benz[d]imidazole derivative (2). Herein, introduction of the benzothiazole moiety was well tolerated by D 2S R and D 3 R binding sites leading to antagonist affinities in the low nanomolar concentration range at both receptor subtypes. However, all novel compounds showed lower antagonist affinity to D 3 R when compared to that of 1. Further exploration of different substitution patterns at the benzothiazole heterocycle and the basic 4-phenylpiperazine resulted in the discovery of high dually acting D 2S R and D 3 R ligands. Moreover, the methoxy substitution at 2-position of 4-phenylpiperazine resulted in significantly (22-fold) increased D 2S R binding affinity as compared to the parent ligand 1, and improved physicochemical and drug-likeness properties of ligands 3-11. However, the latter structural modifications failed to improve the drug-able properties in ligands having un-substituted 4-phenylpiperazine analogs (12)(13)(14)(15)(16)(17)(18)(19)(20). Accordingly, compound 9 showed in addition to high dual affinity at the D 2S R and D 3 R [K i (hD 2S R) = 2.8 ± 0.8 nM; K i (hD 3 R) = 3.0 ± 1.6 nM], promising clogS, clogP, LE (hD 2S R, hD 3 R), LipE (hD 2S R, hD 3 R), and drug-likeness score values of −4.7, 4.2, (0.4, 0.4), (4.4, 4.3), and 0.7, respectively. Also, the deaminated analog 10 [K i (hD 2S R) = 3.2 ± 0.4 nM; K i (hD 3 R) = 8.5 ± 2.2 nM] revealed clogS, clogP, LE (hD 2S R, hD 3 R), LipE (hD 2S R, hD 3 R) and drug-likeness score values of −4.7, 4.2, (0.4, 0.4), (3.9, 3.5), and 0.4, respectively. The results observed for the newly developed benzothiazole-based ligands 3-20 provide clues for the diversity in structure activity relationships (SARs) at the D 2S R and D 3 R subtypes.
Journal of the Serbian Chemical Society, 2019
A total of 14 novel arylpiperazines were synthesized, and pharmacologically evaluated by measuring their affinities towards the D 2 dopamine receptor (DRD2) in a [ 3 H]spiperone competition assay. All the herein described compounds consist of a benzimidazole moiety connected to N-(2-methoxyphenyl)piperazine via linkers of various lengths. Molecular docking analysis and molecular dynamics simulations were performed on the DRD2-arylpiperazine complexes with the objective of exploring the receptor-ligand interactions and properties of the receptor binding site. The recently published crystal structure of DRD2 was used throughout this study. The major finding is that high affinity arylpiperazines must interact with both the orthosteric binding site and the extended binding pocket of DRD2 and therefore should contain a linker of 5 or 6 methylene groups long.
Journal of Medicinal Chemistry, 2004
Recently we reported the pharmacological characterization of the 9,10-dihydropyrrolo[1,3]benzothiazepine derivative (S)-(+)-8 as a novel atypical antipsychotic agent. This compound had an optimum pK i 5-HT 2A /D 2 ratio of 1.21 (pK i 5-HT 2A) 8.83; pK i D 2) 7.79). The lower D 2 receptor affinity of (S)-(+)-8 compared to its enantiomer was explained by the difficulty in reaching the conformation required to optimally fulfill the D 2 pharmacophore. With the aim of finding novel atypical antipsychotics we further investigated the core structure of (S)-(+)-8, synthesizing analogues with specific substituents; the structure-activity relationship (SAR) study was also expanded with the design and synthesis of other analogues characterized by a pyrrolo[2,1-b][1,3]benzothiazepine skeleton, substituted on the benzo-fused ring or on the pyrrole system. On the 9,10-dihydro analogues the substituents introduced on the pyrrole ring were detrimental to affinity for dopamine and for 5-HT 2A receptors, but the introduction of a double bond at C-9/10 on the structure of (S)-(+)-8 led to a potent D 2 /5-HT 2A receptor ligand with a typical binding profile (9f, pK i 5-HT 2A /D 2 ratio of 1.01, log Y) 8.43). Then, to reduce D 2 receptor affinity and restore atypicality on unsaturated analogues, we exploited the effect of specific substitutions on the tricyclic system of 9f. Through a molecular modeling approach we generated a novel series of potential atypical antipsychotic agents, with optimized 5HT 2A /D 2 receptor affinity ratios and that were easier to synthesize and purify than the reference compound (S)-(+)-8. A number of SAR trends were identified, and among the analogues synthesized and tested in binding assays, 9d and 9m were identified as the most interesting, giving atypical log Y scores respectively 4.98 and 3.18 (pK i 5-HT 2A /D 2 ratios of 1.20 and 1.30, respectively). They had a multireceptor affinity profile and could be promising atypical agents. Compound 9d, whose synthesis is easier and whose binding profile is atypical (log Y score similar to that of olanzapine, 3.89), was selected for further biological investigation. Pharmacological and biochemical studies confirmed an atypical antipsychotic profile in vivo. The compound was active on conditioned avoidance response at 1.1 mg/kg, a dose 100-times lower than that required to cause catalepsy (ED 50 >90 mg/kg), it induced a negligible increase of prolactin serum levels after single and multiple doses, and antagonized the cognitive impairment induced by phencyclidine. In conclusion, the pharmacological profile of 9d proved better than clozapine and olanzapine, making this compound a potential clinical candidate.
Journal of Medicinal Chemistry, 2002
ABSTRACT A series of 18 1-[(1,2-diphenyl-1H-4-imidazolyl)methyl]-4-piperazines (1a-r) were designed and synthesized as possible ligands with mixed dopamine (DA) D(2)/serotonin 5-HT(1A) affinity, with the aim of identifying novel compounds with neurochemical and pharmacological properties similar to those of clozapine. The binding profile at D(2) like, 5-HT(1A), and 5-HT(2A) receptors of title compounds was determined. Modifications made in the phenyl rings of the parent compound (1a) produced congeners endowed with a broad range of binding affinities for DA D(2) like, serotonin 5-HT(1A), and 5-HT(2A) receptors, with IC(50) values ranging from 25 to >10,000 nM. As for the modification of the piperazine N(4)-phenyl ring, the affinities for both D(2) like and 5-HT(1A) receptors were progressively increased by introduction of ortho-methoxy and ethoxy groups (1b,o, respectively). Data revealed the presence of a para-chloro substituent in 1g to be associated with a relatively high affinity and substantial selectivity for D(2) like receptors, whereas the meta-chloro analogue 1f exhibited preferential affinity for 5-HT(1A) receptors. A quantitative structure-affinity relationship analysis of the measured binding data resulted in regression equations that highlighted substituent physicochemical properties modulating the binding to subtypes 1A and 2A of serotonin 5-HT receptors but not to D(2) like receptors. Thus, besides an electron-withdrawing field effect and ortho substitution, which both influence binding to serotonin 5-HT receptor subtypes, though to a different extent as revealed by regression coefficients in the multiparametric regression equations, the affinity of congeners 1a-r to 5-HT(1A) receptors proved to be linearly correlated with volume/polarizability descriptors, whereas their affinity to 5-HT(2A) receptors correlated with lipophilicity constants through a parabolic relationship. 1-[(1,2-Diphenyl-1H-4-imidazolyl)methyl]-4-(2-methoxyphenyl)piperazine (1b), with a D(2)/5-HT(1A) IC(50) ratio of approximately 1, was selected for a further pharmacological study. In rats, the intraperitoneal administration of compound 1b, like that of clozapine, induced an increase in the extracellular concentration of DA measured in the medial prefrontal cortex. Furthermore, 1b and clozapine each inhibited GABA-evoked Cl(-) currents at recombinant GABA(A) receptors expressed in Xenopus oocytes. These findings suggest that compound 1b may represent an interesting prototype of a novel class of drugs endowed with a neurochemical profile similar to that of atypical antipsychotics.
Journal of the Serbian Chemical Society, 2018
A total of 14 novel arylpiperazines were synthesized, and pharmacologically evaluated by measuring their affinities towards the D2 dopamine receptor (D2DR) in a [ 3 H]spiperone competition assay. All herein described compounds consist of a benzimidazole moiety connected to the N-(2-methoxyphenyl)piperazine via linkers of various lengths. Molecular docking analysis and molecular dynamics simulations were performed on D2DR-arylpiperazine complexes with an objective to explore the receptor-ligand interactions and properties of the receptor binding site. Crystal structure of D2DR that has been published recently was used throughout this study. The major finding is that high affinity arylpiperazines must interact with both the orthosteric binding site and the extended binding pocket of D2DR and therefore should contain a linker of 5 or 6 methylene groups long.