Azaindole derivatives with high affinity for the dopamine D4 receptor: Synthesis, ligand binding studies and comparison of molecular electrostatic potential maps (original) (raw)
Related papers
European Journal of Medicinal Chemistry, 1999
A series of (3,5-dioxopiperazin-1-yl)ergoline derivatives has been synthesised and evaluated in vitro and in vivo for their dopaminergic D 1 and D 2 components. The structural contributions to the pharmacological profile of the ergoline skeleton, its substituents on positions 1, 2, 6, 9, and the 3,5-dioxopiperazin-1-yl portion of the molecule were examined. Structure-activity relationships within this series suggested that substitution on the ergoline skeleton in position 1 or 2 and on the 3,5-dioxopiperazin-4-nitrogen generated compounds with a spectrum of dopamine agonistic/antagonistic activity sensitive to both the nature and position of substituents. © Elsevier, Paris ergoline derivatives / structure-affinity relationship / dopaminergic / antidopaminergic activity
Research Journal of Pharmaceutical, Biological and Chemical Sciences
An analysis of the relationships between electronic structure and dopamine D 2 receptor binding affinity was carried out for a series of [4-(4-carboxamidobutyl)]-1-arylpiperazines. Local atomic reactivity indices were obtained at the B3LYP/6-31G(d,p) level after full geometry optimization. A statistically significant equation relating several local atomic reactivity indices with the binding affinity was obtained. From the results, a partial 2D pharmacophore is built, containing several sites that can be used for substitution enhancing binding affinity. An important conclusion is that because the common skeleton hypothesis is producing once more excellent results, the results reported here must serve as a guide for correct docking procedures.
Synthesis, binding affinity and SAR of new benzolactam derivatives as dopamine D3 receptor ligands
Bioorganic & Medicinal Chemistry Letters, 2009
A series of new benzolactam derivatives was synthesized and the derivatives were evaluated for their affinities at the dopamine D 1 , D 2 , and D 3 receptors. Some of these compounds showed high D 2 and/or D 3 affinity and selectivity over the D 1 receptor. The SAR study of these compounds revealed structural characteristics that decisively influenced their D 2 and D 3 affinities. Structural models of the complexes between some of the most representative compounds of this series and the D 2 and D 3 receptors were obtained with the aim of rationalizing the observed experimental results. Moreover, selected compounds showed moderate binding affinity on 5-HT 2A which could contribute to reducing the occurrence of extrapyramidal side effects as potential antipsychotics.
Molecular Pharmacology, 2004
We previously demonstrated that, in the D4 dopamine receptor, the aromatic microdomain that spans the interface of the second and third transmembrane segments influences the high-affinity interactions with the D4-selective ligand L750,667 [3-{[4-(4-iodophenyl) piperazin-1yl]methyl}-1H-pyrrolo[2,3-b]pyridine] and the D2-selective ligands methyl-spiperone, aripiprazole, and its congener OPC4392 [7-[3-(4-(2,3-dimethylphenyl) piperazinyl) propoxy] 2-(1H)-quinolinone] . Here we tested a variety of 1,4-disubstituted aromatic piperidines/piperazines (1,4-DAPs) with different subtype selectivities and functional properties against a panel of D4 receptor mutations in the aromatic microdomain to ascertain whether these ligands recognize this common site. Mutant D4 receptors were constructed by substituting the nonconserved amino acid(s) from the corresponding locations in the D2 receptor. The D4-L2.60W, D4-F2.61V, and D4-LM3.28-3.29FV substitutions result in alterations of the relative position of members of the aromatic microdomain. From these results and molecular models of the ligand-receptor complexes, we conclude that 9 of the 11 D4-selective 1,4-DAPs, including L750,667, have a common pattern of ligand-receptor recognition that depends upon favorable interactions with the phenylalanine at position 2.61 (D4-F2.61V, 20-96-fold decrease). Like methylspiperone, aripiprazole, and OPC4392, the two D4-selective 1,4-DAPs that are insensitive to the D4-F2.61V mutation are sensitive to aromatics at position 2.60 (D4-L2.60W, 7-20-fold increase), and they all have longer spacer arms that permit their tethered aromatics to adopt alternative orientations in the binding-site crevice. All 11 of the D4-selective 1,4-DAPs were sensitive to the D4-LM3.28-3.29FV mutation (13-494-fold decrease) but not the moderately D2selective methyl-spiperone. The inferences suggest that subtype selectivity involves two different modes of interaction with the microdomain for the D4-selective 1,4-DAPs and a third mode for D2-selective 1,4-DAPs.
Bioorganic & Medicinal Chemistry Letters, 2006
Aminomethyl-substituted biaryls bearing a pyrazole or triazole moiety were synthesized and investigated for dopamine and serotonin receptor binding. The N-arylpyrazoles 3b,f,g and 4 revealed K i values in the subnanomolar range (0.28-0.70 nM) for the dopamine D4 receptor subtype. Employing both mitogenesis and GTPcS assays, ligand efficacy was evaluated indicating partial agonist properties. Interestingly, the tetrahydropyrimidine 4 (FAUC 2020) displayed significant intrinsic selectivity for D2 long over D2 short .
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 medicinal chemistry, 1989
The synthesis of a structurally novel series of 6,6a,7,8,9,13b-hexahydro-5H-benzo[d]naphtho[2,1-b]azepines (2), conformationally restricted analogues of the dopamine D1 antagonist (5R)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin -7-ol (SCH 23390, 1c), is described. Affinity for D1 receptors was determined by competition for rat striatal binding sites labeled by [3H]SCH 23390; affinity for D2 receptors was similarly determined by competition experiments using [3H]spiperone. Compounds in this series having the B/C-trans ring junction (2b and related analogues), where the D ring is unequivocally fixed in an equatorial orientation, possess considerably more D1 receptor affinity and selectivity vs the D2 receptor than the conformationally mobile cis stereoisomers (2a), thus leading to the conclusion that axial substituents at the 4- or 5-positions of the benzazepine nucleus are detrimental to D1 receptor affinity. Resolution and X-ray analysis demonstrated that D1 recep...
Functionally Selective Dopamine D 2 /D 3 Receptor Agonists Comprising an Enyne Moiety
Journal of Medicinal Chemistry, 2013
Contents 1) 1 Hand 13 C-NMR Data of the Target Compounds……………………………. S2 2) HPLC Data of the Target Compounds…………………………………………. S8 3) Chiral Separation………………………………………………………………… S14 4) X-ray Crystal Structure Determination of 3,5-dinitrobenzamide (S)-7………. S15 5) Dose-Response Curves of the Target Compounds in the [ 35 S]GTPγS Assay… S26 6) Representative Dose-Response Curves of the Reference Compounds Ropinirole and Rotigotine in a [ 35 S]GTPγS Assay with D 2long Expressing Cells………………..… S29 7) Comparison of the Binding Affinities of Representative Compounds at the D 2long Receptor Stably Expressed in CHO Cells and Transiently Expressed in HEK 293 Cells as well as at Membranes from Porcine Striatum………………………………….. S30 8) Amino acid sequence alignment of DRD2, DRD3, 5HT1B and 5HT2B………. S31 S2 1) 1 Hand 13 C-NMR Data and HPLC Data of the Target Compounds (R)-N-{4-[(4-Ethynylcyclohex-3-enyl)propylamino]butyl}biphenyl-4-carboxamide ((R)-1) 1 H-NMR 1 H (600MHz, CD 3 OD) 13 C-NMR 13 C (360MHz, CD 3 OD) S3 (R)-N-{4-[(4-Ethynylcyclohex-3-enyl)propylamino]butyl}pyrazolo[1,5-a]pyridine-2carboxamide ((R)-2a). 1 H-NMR 1 H (600MHz, CDCl 3) 13 C-NMR 13 C (360MHz, CDCl 3) S4 (R)-N-{4-[(4-Ethynylcyclohex-3-enyl)propylamino]butyl}pyrazolo[1,5-a]pyridine-3carboxamide ((R)-2b) 1 H-NMR 1 H (360MHz, CDCl 3) 13 C-NMR 13 C (600MHz, CDCl 3) S5 (R)-4-[3-(1-Butyl-1H-1,2,3-triazol-4-yl)propoxy]-N-{4-[(6-ethynylcyclohex-3enyl)propylamino]-butyl}-3-methoxybenzamide ((R)-2c) 1 H-NMR 1 H (360MHz, CDCl 3) 13 C-NMR 13 C (360MHz, CDCl 3) S6 (R)-N-{4-[(4-Ethynylcyclohex-3-enyl)propylamino]butyl}benzo[b]thiophene-2carboxamide ((R)-2d). 1 H-NMR 1 H (600MHz, CDCl 3) 13 C-NMR 13 C (360MHz, CDCl 3)
Bioorganic & Medicinal Chemistry, 2010
A series of compounds structurally related to aripiprazole (1), an atypical antipsychotic and antidepressant used clinically for the treatment of schizophrenia, bipolar disorder, and depression, have been prepared and evaluated for affinity at D 2-like dopamine receptors. These compounds also share structural elements with the classical D 2-like dopamine receptor antagonists, haloperidol, N-methylspiperone, domperidone and benperidol. Two new compounds, 7-(4-(4-(2methoxyphenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one oxalate (6) and 7-(4-(4-(2-(2-fluoroethoxy)phenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one oxalate were found to (a) bind to the D 2 receptor subtype with high affinity (K i values <0.3 nM), (b) exhibit >50-fold D 2 versus D 3 receptor binding selectivity and (c) be partial agonists at both the D 2 and D 3 receptor subtype.