2-Substituted Nγ-glutamylanilides as novel probes of ASCT2 with improved potency.

Herein, we report the discovery and structure-activity relationships (SAR) of 2-substituted glutamylanilides as novel probes of the steric environment comprising the amino acid binding domain of alanine-serine-cysteine transporter subtype 2 (ASCT2). Focused library development led to three novel, highly potent ASCT2 inhibitors, with N-(2-(morpholinomethyl)phenyl)-L-glutamine exhibiting the greatest potency in a live-cell glutamine uptake assay. This level of potency represents a three-fold improvement over the most potent, previously reported inhibitor in this series, GPNA. Furthermore, this and other compounds in the series exhibit tractable chemical properties for further development as potential therapeutic leads.

Development of an in vivo active, dual EP1 and EP3 selective antagonist based on a novel acyl sulfonamide bioisostere.

Recent preclinical studies demonstrate a role for the prostaglandin E(2) (PGE(2)) subtype 1 (EP1) receptor in mediating, at least in part, the pathophysiology of hypertension and diabetes mellitus. A series of amide and N-acylsulfonamide analogs of a previously described picolinic acid-based human EP1 receptor antagonist (7) were prepared. Each analog had improved selectivity at the mouse EP1 receptor over the mouse thromboxane receptor (TP). A subset of analogs gained affinity for the mouse PGE(2) subtype 3 (EP3) receptor, another potential therapeutic target. One analog (17) possessed equal selectivity for EP1 and EP3, displayed a sufficient in vivo residence time in mice, and lacked the potential for acyl glucuronide formation common to compound 7. Treatment of mice with 17 significantly attenuated the vasopressor activity resulting from an acute infusion of EP1 and EP3 receptor agonists. Compound 17 represents a potentially novel therapeutic in the treatment of hypertension and diabetes mellitus.

Yohimbine depresses excitatory transmission in BNST and impairs extinction of cocaine place preference through orexin-dependent, norepinephrine-independent processes.

The alpha2 adrenergic receptor (α(2)-AR) antagonist yohimbine is a widely used tool for the study of anxiogenesis and stress-induced drug-seeking behavior. We previously demonstrated that yohimbine paradoxically depresses excitatory transmission in the bed nucleus of the stria terminalis (BNST), a region critical to the integration of stress and reward pathways, and produces an impairment of extinction of cocaine-conditioned place preference (cocaine-CPP) independent of α(2)-AR signaling. Recent studies show yohimbine-induced drug-seeking behavior is attenuated by orexin receptor 1 (OX(1)R) antagonists. Moreover, yohimbine-induced cocaine-seeking behavior is BNST-dependent. Here, we investigated yohimbine-orexin interactions. Our results demonstrate yohimbine-induced depression of excitatory transmission in the BNST is unaffected by alpha1-AR and corticotropin-releasing factor receptor-1 (CRFR(1)) antagonists, but is (1) blocked by OxR antagonists and (2) absent in brain slices from orexin knockout mice. Although the actions of yohimbine were not mimicked by the norepinephrine transporter blocker reboxetine, they were by exogenously applied orexin A. We find that, as with yohimbine, orexin A depression of excitatory transmission in BNST is OX(1)R-dependent. Finally, we find these ex vivo effects are paralleled in vivo, as yohimbine-induced impairment of cocaine-CPP extinction is blocked by a systemically administered OX(1)R antagonist. These data highlight a new mechanism for orexin on excitatory anxiety circuits and demonstrate that some of the actions of yohimbine may be directly dependent upon orexin signaling and independent of norepinephrine and CRF in the BNST.

Continued optimization of the MLPCN probe ML071 into highly potent agonists of the hM1 muscarinic acetylcholine receptor.

This Letter describes the continued optimization of the MLPCN probe molecule ML071. After introducing numerous cyclic constraints and novel substitutions throughout the parent structure, we produced a number of more highly potent agonists of the M(1) mACh receptor. While many novel agonists demonstrated a promising ability to increase soluble APPα release, further characterization indicated they may be functioning as bitopic agonists. These results and the implications of a bitopic mode of action are presented.

Discovery and SAR of 6-substituted-4-anilinoquinazolines as non-competitive antagonists of mGlu5.

A high-throughput cell-based screen identified a series of 6-substituted-4-anilinoquinazolines as non-competitive antagonists of metabotropic glutamate receptor 5 (mGlu(5)). This Letter describes the SAR of this series and the profile of selected compounds in selectivity and radioligand binding assays.