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.

Metabotropic glutamate receptor 7 (mGlu7) is a member of the group III mGlu receptors (mGlus), encompassed by mGlu4, mGlu6, mGlu7, and mGlu8. mGlu7 is highly expressed in the presynaptic active zones of both excitatory and inhibitory synapses, and activation of the receptor regulates the release of both glutamate and GABA. mGlu7 is thought to be a relevant therapeutic target for a number of neurological and psychiatric disorders, and polymorphisms in the GRM7 gene have been linked to autism, depression, ADHD, and schizophrenia. Here we report two new pan-group III mGlu positive allosteric modulators, VU0155094 and VU0422288, which show differential activity at the various group III mGlus. Additionally, both compounds show probe dependence when assessed in the presence of distinct orthosteric agonists. By pairing studies of these nonselective compounds with a synapse in the hippocampus that expresses only mGlu7, we have validated activity of these compounds in a native tissue setting. These studies provide proof-of-concept evidence that mGlu7 activity can be modulated by positive allosteric modulation, paving the way for future therapeutics development.

Herein, we detail the optimization of the mGlu NAM, VU0650786, via a reductionist approach to afford a novel, simplified mGlu NAM scaffold that engenders potent and selective mGlu inhibition (mGlu IC = 245 nM, mGlu IC > 30 μM) with excellent central nervous system penetration (rat brain/plasma = 1.2, = 0.40). Moreover, this new chemotype, exemplified by VU6010572, requires only four synthetic steps and displays improved physiochemical properties and efficacy in a mouse tail suspension test (MED = 3 mg/kg i.p.).

This work describes the discovery and characterization of novel 6-(1Hpyrazolo[4,3-b]pyridin-3-yl)amino-benzo[d]isothiazole-3-carboxamides as mGlu 4 PAMs. This scaffold provides improved metabolic clearance and CYP1A2 profiles compared to previously discovered mGlu 4 PAMs. From this work, 27o (VU6001376) was identified as a potent (EC 50 = 50.1 nM, 50.5% GluMax) and selective mGlu 4 PAM with an excellent rat DMPK profile (in vivo rat CL p = 3.1 mL/min/kg, t 1/2 = 445 min, CYP1A2 IC 50 > 30 μM). Compound 27o was also active in reversing haloperidol induced catalepsy in a rodent preclinical model of Parkinson's disease.

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