Tag: M.W=300-350

Floresca, Christina Z. published the artcileReciprocal mutations in TM2/TM3 in a D2 dopamine receptor background confirms the importance of this microdomain as a selective determinant of para-halogenated 1,4-disubstituted aromatic piperazines, COA of Formula: C18H19ClN4, the publication is Archiv der Pharmazie (Weinheim, Germany) (2005), 338(5-6), 268-275, database is CAplus and MEDLINE.

The authors recently demonstrated that in the D4 dopamine receptor the aromatic microdomain that spans the interface of the second and third transmembrane (TM) domains influences the high affinity interactions of extremely D4-selective ligands possessing a 1,4-disubstituted aromatic piperazine/piperidine (1,4-DAP) structure. On the basis of their substructural features and patterns of sensitivity to mutations constructed in a D4 receptor background, the D4-selective 1,4-DAPs were categorized as having two distinct modes of binding that the authors named mode-1 and mode-3. Here the authors extend these findings of the ligand-receptor structure-affinity relationships for some of these highly D4-selective 1,4-DAPs by measuring the effect of the corresponding reciprocal TM2/TM3 mutations constructed in a D2 dopamine receptor background on the binding affinity of the para-halogenated mode-1 ligands L750,667 and FAUC213. The results indicate that the D2-V2.61F+FV3.28-3.29LM mutant binds L750,667 and FAUC213 with significantly increased affinity, i.e., its binding profile becomes more D4-like. These findings further support the assignment of the TM2/TM3 aromatic microdomain encompassing positions 2.61 and 3.28-3.29 as a 1,4-DAP D4-selectivity microdomain and highlights the importance of the precise emplacement of aromatics in this microdomain as key to the selective mol. recognition of L750,667 and FAUC213.

Archiv der Pharmazie (Weinheim, Germany) 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, COA of Formula: C18H19ClN4.

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

Stewart, Andrew O. published the artcileDopamine D₄ ligands and models of receptor activation: 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole and related heteroarylmethylarylpiperazines exhibit a substituent effect responsible for additional efficacy tuning, Formula: C18H19ClN4, the publication is Journal of Medicinal Chemistry (2004), 47(9), 2348-2355, database is CAplus and MEDLINE.

A series of subtype selective dopamine D₄ receptor ligands from the heteroarylmethylphenylpiperazine class have been discovered that exhibit a remarkable structure-activity relation (SAR), revealing a substituent effect in which regiosubstitution on the terminal arylpiperazine ring can modulate functional or intrinsic activity. Other structure-dependent efficacy studies in the dopamine D₄ field have suggested a critical interaction of the heteroarylmethyl moiety with specific protein microdomains in controlling intrinsic activity. The authors studies indicate that for some binding orientations, the phenylpiperazine moiety also plays a key role in determining efficacy. These data also implicate a kinetic or efficiency term, contained within measured functional affinities for agonists, which support a sequential binding and conformational stabilization model for receptor activation. The structural similarity between partial agonist and antagonist, within this subset of ligands, and lack of bioisosterism for this substituent effect are key phenomena for these hypotheses.

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 C16H20N2, Formula: C18H19ClN4.

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

Ericksen, Spencer S. published the artcileLigand selectivity of D₂ dopamine receptors is modulated by changes in local dynamics produced by sodium binding, COA of Formula: C18H19ClN4, the publication is Journal of Pharmacology and Experimental Therapeutics (2009), 328(1), 40-54, database is CAplus and MEDLINE.

We have uncovered a significant allosteric response of the D₂ dopamine receptor to physiol. relevant concentrations of sodium (140 mM), characterized by a sodium-enhanced binding affinity for a D₄-selective class of agonists and antagonists. This enhancement is significantly more pronounced in a D₂-V2.61(91)F mutant and cannot be mimicked by an equivalent concentration of the sodium replacement cation N-methyl-D-glucamine. This phenomenon was explored computationally at the mol. level by analyzing the effect of sodium binding on the dynamic properties of D₂ receptor model constructs. Normal mode anal. identified one mode (M₁₉), which is involved in the open/closed motions of the binding cleft as being particularly sensitive to the sodium effect. To examine the consequences for D₂ receptor ligand recognition, one of the ligands, L-745,870 [3-{[4-(4-chlorophenyl) piperazin-1-yl]methyl}-1H-pyrrolo[2,3-b]pyridine or CPPMA, chlorophenylpiperazinyl methylazaindole], was docked into conformers along the M₁₉ trajectory. Structurally and pharmacol. well established ligand-receptor interactions, including the ionic interaction with D3.32(114) and interactions between the ligand aryl moieties and V2.61(91)F, were achieved only in “open” phase conformers. The docking of (-)-raclopride [3,5-dichloro-N-(1-ethylpyrrolidin-2-ylmethyl)-2-hydroxy-6-methoxybenzamide] suggests that the same binding cleft changes in response to sodium-binding perturbation account as well for the enhancements in binding affinity for substituted benzamides in the wild-type D₂ receptor. Our findings demonstrate how key interactions can be modulated by occupancy at an allosteric site and are consistent with a mechanism in which sodium binding enhances the affinity of selected ligands through dynamic changes that increase accessibility of substituted benzamides and 1,4-DAP ligands to the orthosteric site and accessibility of 1,4-DAPs to V2.61(91)F.

Journal of Pharmacology and Experimental Therapeutics 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, COA of Formula: C18H19ClN4.

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