Examining the Role of the Linker in Bitopic -Substituted Adenosine Derivatives Acting as Biased Adenosine A Receptor Agonists.

The adenosine A receptor is a therapeutic target based on its ability to provide cardioprotection during episodes of myocardial ischemia and reperfusion injury. However, the clinical translation of AR agonists has been hindered by dose-limiting adverse effects (bradycardia and hypotension). Previously, we demonstrated that the bitopic agonist VCP746 (), consisting of an adenosine pharmacophore linked to an allosteric moiety, can stimulate cardioprotective AR signaling effects in the absence of unwanted bradycardia.

Enantioenriched Positive Allosteric Modulators Display Distinct Pharmacology at the Dopamine D Receptor.

(1) Background: Two first-in-class racemic dopamine D receptor (DR) positive allosteric modulator (PAM) chemotypes ( and ) were identified from a high-throughput screen. In particular, due to its selectivity for the DR and reported lack of intrinsic activity, compound shows promise as a starting point toward the development of small molecule allosteric modulators to ameliorate the cognitive deficits associated with some neuropsychiatric disease states; (2) Methods: Herein, we describe the enantioenrichment of optical isomers of using chiral auxiliaries derived from ()- and ()-3-hydroxy-4,4-dimethyldihydrofuran-2(3)-one (d- and l-pantolactone, respectively); (3) Results: We confirm both the racemate and enantiomers of are active and selective for the DR, but that the respective stereoisomers show a significant difference in their affinity and magnitude of positive allosteric cooperativity with dopamine; (4) Conclusions: These data warrant further investigation of asymmetric syntheses of optically pure analogues of for the development of DR PAMs with superior allosteric properties.

Structure-Kinetic Profiling of Haloperidol Analogues at the Human Dopamine D Receptor.

Haloperidol is a typical antipsychotic drug (APD) associated with an increased risk of extrapyramidal side effects (EPSs) and hyperprolactinemia relative to atypical APDs such as clozapine. Both drugs are dopamine D receptor (DR) antagonists, with contrasting kinetic profiles. Haloperidol displays fast association/slow dissociation at the DR, whereas clozapine exhibits relatively slow association/fast dissociation.

Subtle modifications to a thieno[2,3-d]pyrimidine scaffold yield negative allosteric modulators and agonists of the dopamine D receptor.

We recently described a structurally novel series of negative allosteric modulators (NAMs) of the dopamine D receptor (DR) based on thieno[2,3-d]pyrimidine 1, showing it can be structurally simplified to reveal low molecular weight, fragment-like NAMs that retain robust negative cooperativity, such as 3. Herein, we report the synthesis and functional profiling of analogues of 3, placing specific emphasis on examining secondary and tertiary amino substituents at the 4-position, combined with a range of substituents at the 5/6-positions (e.g.

Identification of Positive Allosteric Modulators of the D Dopamine Receptor That Act at Diverse Binding Sites.

The D dopamine receptor is linked to a variety of neuropsychiatric disorders and represents an attractive drug target for the enhancement of cognition in schizophrenia, Alzheimer disease, and other disorders. Positive allosteric modulators (PAMs), with their potential for greater selectivity and larger therapeutic windows, may represent a viable drug development strategy, as orthosteric D receptor agonists possess known clinical liabilities. We discovered two structurally distinct D receptor PAMs, MLS6585 and MLS1082, via a high-throughput screen of the NIH Molecular Libraries program small-molecule library.

A Thieno[2,3- d]pyrimidine Scaffold Is a Novel Negative Allosteric Modulator of the Dopamine D Receptor.

Recently, a novel negative allosteric modulator (NAM) of the D-like dopamine receptors 1 was identified through virtual ligand screening. This ligand comprises a thieno[2,3- d]pyrimidine scaffold that does not feature in known dopaminergic ligands. Herein, we provide pharmacological validation of an allosteric mode of action for 1, revealing that it is a NAM of dopamine efficacy and identify the structural determinants of this allostery.