Tag: M.W=300-350

Boeckler, Frank published the artcileModeling the Similarity and Divergence of Dopamine D₂-like Receptors and Identification of Validated Ligand-Receptor Complexes, Quality Control of 337972-47-1, the publication is Journal of Medicinal Chemistry (2005), 48(3), 694-709, database is CAplus and MEDLINE.

Focusing on the similarity and divergence of GPCR subtypes and their ligand interactions, we generated dopamine D₂, D₃, and D₄ receptor models based on the rhodopsin crystal structure and refined these with an extensive MM/MD protocol. After validation by diagnostic exptl. data, subtype-specific relative positions of TM1, 2, 6, and 7 and bending angles of TM7 were found. To sample the conformational space of the complex, we performed simulated-annealing runs of the receptor protein with the sub-nanomolar antagonist spiperone. Docking a representative set of ligands, we were able to identify one superior model for each subtype when excellent correlations between predicted energies of binding and exptl. affinities (r² = 0.72 for D₂, 0.91 for D₃ and 0.77 for D₄) could be observed Further anal. revealed general ligand interactions with ASP3.32 and aromatic residues in TM6/7 and individual key interactions with TM1 and TM2 residues of the D₃ and D₄ receptor models, resp.

Journal of Medicinal Chemistry published new progress about 337972-47-1. 337972-47-1 belongs to piperazines, auxiliary class Inhibitor, name is 2-((4-(4-Chlorophenyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridine, and the molecular formula is C18H19ClN4, Quality Control of 337972-47-1.

Referemce:
https://en.wikipedia.org/wiki/Piperazine,
Piperazines – an overview | ScienceDirect Topics

Loeber, Stefan published the artcileRationally Based Efficacy Tuning of Selective Dopamine D4 Receptor Ligands Leading to the Complete Antagonist 2-[4-(4-Chlorophenyl)piperazin-1-ylmethyl]pyrazolo[1,5-a]pyridine (FAUC 213), Related Products of piperazines, the publication is Journal of Medicinal Chemistry (2001), 44(17), 2691-2694, database is CAplus and MEDLINE.

Structure dependent efficacy studies in the field of selective D4 ligands led to the 2-aminomethyl substituted azaindole 2 (FAUC 213) that displayed strong D4 binding, high subtype selectivity, and complete antagonist properties in ligand-induced mitogenesis experiments According to our schematic mol. model, the intrinsic activity of the regioisomers investigated is controlled by the ability of the heterocyclic unit to interact with both elements of the D4 binding-site crevice, the aromatic microdomain in TM6, and a serine residue in TM5.

Journal of Medicinal Chemistry published new progress about 337972-47-1. 337972-47-1 belongs to piperazines, auxiliary class Inhibitor, name is 2-((4-(4-Chlorophenyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridine, and the molecular formula is C18H19ClN4, Related Products of piperazines.

Referemce:
https://en.wikipedia.org/wiki/Piperazine,
Piperazines – an overview | ScienceDirect Topics

Cramer, Richard D. published the artcile“Lead Hopping”. Validation of Topomer Similarity as a Superior Predictor of Similar Biological Activities, Safety of 2-((4-(4-Chlorophenyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridine, the publication is Journal of Medicinal Chemistry (2004), 47(27), 6777-6791, database is CAplus and MEDLINE.

Two extensive studies quantifying the ability of topomer shape similarity to forecast a variety of biol. similarities are described. In a prospective trial of “lead hopping”, using topomer similarity for virtual screening and queries from the patent literature, biol. assays of 308 selected compounds (representing 0.03% of those available, per assay type) yielded 11 successful “lead hops” in the 13 assays attempted. The hit rate averaged over all assays was 39% (“activity” defined as inhibition ≥20% at 10 μM), significantly greater than an unexpectedly high neg. control hit rate of 15%. The average “Tanimoto 2D fingerprint similarity” between query and “lead hop” structures (0.36) was little more than the Tanimoto similarity between random drug-like structures. Topomer shape and Tanimoto 2D fingerprint similarities were also compared retrospectively, in their tendencies to concentrate together potential and actual drugs reported to belong to the same “activity class”, for twenty classes. Among the most similar 3% of structures (corresponding to “≥0.85 Tanimoto” for these structures), an average of 62% of the topomer similar selection possessed a near neighbor belonging to the same activity class, roughly a one-third superiority over the “Tanimoto ≥ 0.85” selection containing 48% actives in avoiding false positives. Conversely, the least similar 75% of structures contained 0.3% actives for topomer similarity vs. 1.0% actives for Tanimoto 2D fingerprint similarity, a 3-fold superiority for topomers in avoiding false negatives.

Journal of Medicinal Chemistry published new progress about 337972-47-1. 337972-47-1 belongs to piperazines, auxiliary class Inhibitor, name is 2-((4-(4-Chlorophenyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridine, and the molecular formula is C18H19ClN4, Safety of 2-((4-(4-Chlorophenyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridine.

Referemce:
https://en.wikipedia.org/wiki/Piperazine,
Piperazines – an overview | ScienceDirect Topics

Kortagere, Sandhya published the artcileCertain 1,4-disubstituted aromatic piperidines and piperazines with extreme selectivity for the dopamine D4 receptor interact with a common receptor microdomain, Category: piperazines, the publication is Molecular Pharmacology (2004), 66(6), 1491-1499, database is CAplus and MEDLINE.

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-1-yl]methyl}-1H-pyrrolo[2,3-b]pyridine] and the D2-selective ligands methylspiperone, aripiprazole, and its congener OPC4392 [7-[3-(4-(2,3-dimethylphenyl)piperazinyl)propoxy]2-(1H)-quinolinone] (Schetz et al., 2000). 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 mol. 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 D2-selective methylspiperone. 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.

Molecular Pharmacology published new progress about 337972-47-1. 337972-47-1 belongs to piperazines, auxiliary class Inhibitor, name is 2-((4-(4-Chlorophenyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridine, and the molecular formula is C18H19ClN4, Category: piperazines.

Referemce:
https://en.wikipedia.org/wiki/Piperazine,
Piperazines – an overview | ScienceDirect Topics

Ehrlich, Katharina published the artcileDopamine D₂, D₃, and D₄ Selective Phenylpiperazines as Molecular Probes To Explore the Origins of Subtype Specific Receptor Binding, Recommanded Product: 2-((4-(4-Chlorophenyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridine, the publication is Journal of Medicinal Chemistry (2009), 52(15), 4923-4935, database is CAplus and MEDLINE.

Assembling phenylpiperazines with 7a-azaindole via different spacer elements, we developed subtype selective dopamine receptor ligands, e.g. I, preferentially interacting with D₄, D₂, and D₃, resp. To complete this set, the methylthio analogs exceeding the affinity of methoxy derivatives by one order of magnitude and a structural intermediate II were synthesized. These chem. similar but biol. divergent target compounds served as mol. probes for radioligand displacement experiments, mutagenesis, and docking studies on homol. models based on the recent crystal structure of the β₂-adrenergic receptor. Specific interactions with the highly conserved amino acids Asp^3.32 and His^6.55 and less conserved residues at positions 2.61, 2.64, 3.28, and 3.29 were identified. Inclusion of a carefully modeled extracellular loop 2 displayed two nonconserved residues in EL2 that differently contribute to ligand binding. Obviously, subtype selectivity is caused by nonconserved but frequently mediated by conserved amino acids.

Journal of Medicinal Chemistry published new progress about 337972-47-1. 337972-47-1 belongs to piperazines, auxiliary class Inhibitor, name is 2-((4-(4-Chlorophenyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridine, and the molecular formula is C18H19ClN4, Recommanded Product: 2-((4-(4-Chlorophenyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridine.

Referemce:
https://en.wikipedia.org/wiki/Piperazine,
Piperazines – an overview | ScienceDirect Topics

Salama, Ismail published the artcileStructure-Selectivity Investigations of D₂-Like Receptor Ligands by CoMFA and CoMSIA Guiding the Discovery of D₃ Selective PET Radioligands, Product Details of C18H19ClN4, the publication is Journal of Medicinal Chemistry (2007), 50(3), 489-500, database is CAplus and MEDLINE.

Elucidation of the physiol. role of the D₃ receptor and its distribution in the brain using positron emission tomog. (PET) is hampered by the lack of bioavailable subtype selective tracer ligands. To develop appropriate D₃ radioligands, we designed an integrative procedure involving the elucidation of structural features determining D₃ selectivity over both congeners D₂ and D₄ by comparative mol. anal. Thus, we have successfully generated CoMFA and CoMSIA models based on the affinity differences of a series of 79 ligands representing a broad range of selectivities. These models yielded highly significant cross-validations (q²_cv(D₃/D₂) = 0.86; q²_cv(D₃/D₄) = 0.92) and excellent predictions of a 16-ligand test set (r²_pred = 0.79-0.93). Exploiting this information, synthesis and receptor binding studies directed us to the fluorinated lead compounds 78 and 79, featuring subnanomolar D₃ affinities and considerable selectivities over D₂ and D₄ and, subsequently, to the subtype selective PET tracers [¹⁸F]78 and [¹⁸F]79.

Journal of Medicinal Chemistry published new progress about 337972-47-1. 337972-47-1 belongs to piperazines, auxiliary class Inhibitor, name is 2-((4-(4-Chlorophenyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridine, and the molecular formula is C18H19ClN4, Product Details of C18H19ClN4.

Referemce:
https://en.wikipedia.org/wiki/Piperazine,
Piperazines – an overview | ScienceDirect Topics

Cummings, David F. published the artcileThree amino acids in the D₂ dopamine receptor regulate selective ligand function and affinity, Related Products of piperazines, the publication is Journal of Neurochemistry (2009), 110(1), 45-57, database is CAplus and MEDLINE.

The D₂ dopamine receptor is an important therapeutic target for the treatment of psychotic, agitated, and abnormal behavioral states. To better understand the specific interactions of subtype-selective ligands with dopamine receptor subtypes, seven ligands with high selectivity (>120-fold) for the D₄ subtype of dopamine receptor were tested on wild-type and mutant D₂ receptors. Five of the selective ligands were observed to have 21-fold to 293-fold increases in D₂ receptor affinity when three non-conserved amino acids in TM2 and TM3 were mutated to the corresponding D₄ amino acids. The two ligands with the greatest improvement in affinity for the D₂ mutant receptor [i.e., 3-([4-(4-iodophenyl) piperazin-1-yl]methyl)-1H-pyrrolo[2,3-b]pyridine (L-750,667) and 1-[4-iodobenzyl]-4-[N-(3-isopropoxy-2-pyridinyl)-N-methyl]- aminopiperidine (RBI-257)] were investigated in functional assays. Consistent with their higher affinity for the mutant than for the wild-type receptor, concentrations of L-750,667 or RBI-257 that produced large reductions in the potency of quinpirole’s functional response in the mutant did not significantly reduce quinpirole’s functional response in the wild-type D₂ receptor. In contrast to RBI-257 which is an antagonist at all receptors, L-750,667 is a partial agonist at the wild-type D₂ but an antagonist at both the mutant D₂ and wild-type D₄ receptors. Our study demonstrates for the first time that the TM2/3 microdomain of the D₂ dopamine receptor not only regulates the selective affinity of ligands, but in selected cases can also regulate their function. Utilizing a new docking technique that incorporates receptor backbone flexibility, the three non-conserved amino acids that encompass the TM2/3 microdomain were found to account in large part for the differences in intermol. steric contacts between the ligand and receptors. Consistent with the exptl. data, this model illustrates the interactions between a variety of subtype-selective ligands and the wild-type D₂, mutant D₂, or wild-type D₄ receptors.

Journal of Neurochemistry published new progress about 337972-47-1. 337972-47-1 belongs to piperazines, auxiliary class Inhibitor, name is 2-((4-(4-Chlorophenyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridine, and the molecular formula is C18H19ClN4, Related Products of piperazines.

Referemce:
https://en.wikipedia.org/wiki/Piperazine,
Piperazines – an overview | ScienceDirect Topics