Insecticide resistance is a growing threat to mosquito control programs around the world, thus creating the need to discover novel target sites and target-specific compounds for insecticide development. Emerging evidence suggests that mosquito inward rectifier potassium (Kir) channels represent viable molecular targets for developing insecticides with new mechanisms of action. Here we describe the discovery and characterization of VU041, a submicromolar-affinity inhibitor of Anopheles (An.) gambiae and Aedes (Ae.) aegypti Kir1 channels that incapacitates adult female mosquitoes from representative insecticide-susceptible and -resistant strains of An. gambiae (G3 and Akron, respectively) and Ae. aegypti (Liverpool and Puerto Rico, respectively) following topical application. VU041 is selective for mosquito Kir channels over several mammalian orthologs, with the exception of Kir2.1, and is not lethal to honey bees. Medicinal chemistry was used to develop an analog, termed VU730, which retains activity toward mosquito Kir1 but is not active against Kir2.1 or other mammalian Kir channels. Thus, VU041 and VU730 are promising chemical scaffolds for developing new classes of insecticides to combat insecticide-resistant mosquitoes and the transmission of mosquito-borne diseases, such as Zika virus, without harmful effects on humans and beneficial insects.

Highly selective positive allosteric modulators (PAMs) of the M subtype of muscarinic acetylcholine receptor have emerged as an exciting new approach for improving cognitive function in patients suffering from Alzheimer's disease and schizophrenia. However, excessive activation of M is known to induce seizure activity and have actions in the prefrontal cortex (PFC) that could impair cognitive function. We now report a series of pharmacological, electrophysiological, and behavioral studies in which we find that recently reported M PAMs, PF-06764427 and MK-7622, have robust agonist activity in cell lines and agonist effects in the mouse PFC, and have the potential to overactivate the M receptor and disrupt PFC function. In contrast, structurally distinct M PAMs (VU0453595 and VU0550164) are devoid of agonist activity in cell lines and maintain activity dependence of M activation in the PFC. Consistent with the previously reported effect of PF-06764427, the ago-PAM MK-7622 induces severe behavioral convulsions in mice. In contrast, VU0453595 does not induce behavioral convulsions at doses well above those required for maximal efficacy in enhancing cognitive function. Furthermore, in contrast to the robust efficacy of VU0453595, the ago-PAM MK-7622 failed to improve novel object recognition, a rodent assay of cognitive function. These findings suggest that in vivo cognition-enhancing efficacy of M PAMs can be observed with PAMs lacking intrinsic agonist activity and that intrinsic agonist activity of M PAMs may contribute to adverse effects and reduced efficacy in improving cognitive function.

Both historical clinical and recent preclinical data suggest that the M1 muscarinic acetylcholine receptor is an exciting target for the treatment of Alzheimer’s disease and the cognitive and negative symptom clusters in schizophrenia; however, early drug discovery efforts targeting the orthosteric binding site have failed to afford selective M1 activation. Efforts then shifted to focus on selective activation of M1 via either allosteric agonists or positive allosteric modulators (PAMs). While M1 PAMs have robust efficacy in rodent models, some chemotypes can induce cholinergic adverse effects (AEs) that could limit their clinical utility. Here, we report studies aimed at understanding the subtle structural and pharmacological nuances that differentiate efficacy from adverse effect liability within an indole-based series of M1 ago-PAMs. Our data demonstrate that closely related M1 PAMs can display striking differences in their in vivo activities, especially their propensities to induce adverse effects. We report the discovery of a novel PAM in this series that is devoid of observable adverse effect liability. Interestingly, the molecular pharmacology profile of this novel PAM is similar to that of a representative M1 PAM that induces severe AEs. For instance, both compounds are potent ago-PAMs that demonstrate significant interaction with the orthosteric site (either bitopic or negative cooperativity). However, there are subtle differences in efficacies of the compounds at potentiating M1 responses, agonist potencies, and abilities to induce receptor internalization. While these differences may contribute to the differential in vivo profiles of these compounds, the in vitro differences are relatively subtle and highlight the complexities of allosteric modulators and the need to focus on in vivo phenotypic screening to identify safe and effective M1 PAMs.

Parkinson's disease (PD) is a debilitating neurodegenerative disorder associated with severe motor impairments caused by the loss of dopaminergic innervation of the striatum. Previous studies have demonstrated that positive allosteric modulators (PAMs) of metabotropic glutamate receptor 4 (mGlu 4 ), including N-phenyl-7-(hydroxyimino)cyclopropa [b]chromen-1a-carboxamide, can produce antiparkinsonian-like effects in preclinical models of PD. However, these early mGlu 4 PAMs exhibited unsuitable physiochemical properties for systemic dosing, requiring intracerebroventricular administration and limiting their broader utility as in vivo tools to further understand the role of mGlu 4 in the modulation of basal ganglia function relevant to PD. In the present study, we describe the pharmacologic characterization of a systemically active mGlu 4 PAM, N-(3-chlorophenyl)picolinamide (VU0364770), in several rodent PD models. VU0364770 showed efficacy alone or when administered in combination with L-DOPA or an adenosine 2A (A 2A ) receptor antagonist currently in clinical development (preladenant). When administered alone, VU0364770 exhibited efficacy in reversing haloperidol-induced catalepsy, forelimb asymmetry-induced by unilateral 6-hydroxydopamine (6-OHDA) lesions of the median forebrain bundle, and attentional deficits induced by bilateral 6-OHDA nigrostriatal lesions in rats. In addition, VU0364770 enhanced the efficacy of preladenant to reverse haloperidol-induced catalepsy when given in combination. The effects of VU0364770 to reverse forelimb asymmetry were also potentiated when the compound was coadministered with an inactive dose of L-DOPA, suggesting that mGlu 4 PAMs may provide L-DOPA-sparing activity. The present findings provide exciting support for the potential role of selective mGlu 4 PAMs as a novel approach for the symptomatic treatment of PD and a possible augmentation strategy with either L-DOPA or A 2A antagonists.

We report the synthesis and evaluation of a series of heterobiaryl amides as positive allosteric modulators of mGluR4. Compounds 9b and 9c showed submicromolar potency at both human and rat mGluR4. In addition, both 9b and 9c were shown to be centrally penetrant in rats using nontoxic vehicles, a major advance for the mGluR4 field.The metabotropic glutamate receptors (mGluRs a ) are members of the GPCR family C, characterized by a large extracellular amino-terminal binding domain (agonist) along with a 7-transmembrane spanning (7TM) domain which is the binding site for most known mGluR allosteric modulators. [1][2][3] The eight cloned mGluRs have been assigned to three groups (Groups I,II,III) based on their structural similarity, ligand specificity, and preferred coupling mechanisms. 4 The Group I subfamily is composed of mGluR1 and mGluR5; Group II receptors include mGluR2 and mGluR3; and the Group III receptors are represented by mGluR4, mGluR6, mGluR7 and mGluR8. Among the mGluRs, the Group III receptors have thus far received less attention in terms of their therapeutic potential due to the paucity of selective ligands. However, recently there have been numerous reports detailing the potential benefits of mGluR4 activation in several disease models, most notably rodent models of Parkinson's disease. 5,6 It has been shown that activation of mGluR4 decreases GABAergic transmission at the inhibitory striato-pallidal synapse with the basal ganglia, a mechanism that is expected to provide palliative benefit for the treatment of Parkinson's disease. 7 In addition, there have been recent reports detailing the neuroprotective effects of an mGluR4 PAM in cultured neurons and in vivo. 8 The most well characterized mGluR4 PAM for many years has been the compound PHCCC, 1, a partially selective mGluR4 potentiator. 8,10,11 More recently, our laboratory and others have expanded the list of novel probes for positive allosteric modulation of mGluR4 ( Figure 1). [12][13][14][15][16] Unfortunately, all of the disclosed mGluR4 PAMs are deficient in their penetration into the CNS and their effects have only been demonstrated via intracerebroventricular (icv) injection or with the use of toxic vehicles such as a 50% DMSO solution. Herein, we report a class of centrally penetrant mGluR4 PAMs which can be administered in a nontoxic vehicle.A high-throughput screening (HTS) campaign was initiated at Vanderbilt to identify novel mGluR4 PAMs. [12][13][14] In addition to the ligands shown in Figure 1, there were a number of small aryl amide compounds identified as having mGluR4 PAM activity (Figure 2). These were attractive hits due to their favorable calculated properties (MW <300, cLogP <3.50, total Polar Surface Area (tPSA) <40, Ligand Efficiency (LE) 17 >0.30). From these lead compounds we initiated an optimization program in order to further profile this chemical series as novel mGluR4 PAMs.Initial effort was directed at the left-side heteroaryl amide portion for which the synthesis is outlined in Scheme 1. A small ...