Selective activation of the M4 muscarinic acetylcholine receptor subtype offers a novel strategy for the treatment of psychosis in multiple neurological disorders. Although the development of traditional muscarinic activators has been stymied due to pan-receptor activation, muscarinic receptor subtype selectivity can be achieved through the utilization of a subtype of a unique allosteric site. A major challenge in capitalizing on this allosteric site to date has been achieving a balance of suitable potency and brain penetration. Herein, we describe the design of a brain penetrant series of M4 selective positive allosteric modulators (PAMs), ultimately culminating in the identification of 21 (PF-06852231, now CVL-231/emraclidine), which is under active clinical development as a novel mechanism and approach for the treatment of schizophrenia.

A loss-of-function polymorphism in the α5 nicotinic acetylcholine receptor (nAChR) subunit gene has been linked to both drug abuse and schizophrenia. The α5 nAChR subunit is strategically positioned in the prefrontal cortex (PFC), where a loss-of-function in this subunit may contribute to cognitive disruptions in both disorders. However, the specific contribution of α5 to PFC-dependent cognitive functions has yet to be illustrated. In the present studies, we used RNA interference to knockdown the α5 nAChR subunit in the PFC of adult rats. We provide evidence that through its contribution to cholinergic modulation of cholinergic modulation of neurons in the PFC, the α5 nAChR plays a specific role in the recovery of attention task performance following distraction. Our combined data reveal the potent ability of this subunit to modulate the PFC and cognitive functions controlled by this brain region that are impaired in disease.

Increasing evidence associates dysfunctional dopamine signaling with the motor and cognitive deficits in Alzheimer's disease. While D1 receptor (D1R) specific pathologies are reported, current D1R compounds have limited therapeutic potential due to their poor CNS penetration, negligible oral bioavailability, rapid metabolism and propensity to cause receptor desensitization. We describe here a novel class of D1R agonists that show reduced receptor desensitization in vitro as well as reduced tachyphylaxis in vivo. For in vitro D1 receptor desensitization experiments cAMP activity was measured from rat striatal neurons using the Cisbio HTRF cAMP dynamic range assay kit. For in vivo testing of tachyphylaxis, Sprague-Dawley rats with unilateral 6-OHDA lesions (n=17) were individually monitored for rotational behavior using infrared cameras and dosed using a crossover design (2-week washout period) in their home cages. In each treatment period animals received six doses of either a catechol (A-77636, 0.32 mg/kg S.C.) or non-catechol (PF-2334, 10.78 mg/kg, P.O.) D1R agonist administered every 12 h followed by a single dose of the D2 agonist quinpirole (0.1 mg/kg S.C.). In vitro, pre-treatment with catecholamine agonists (dopamine, A-77636, dihydrexidine, or SKF-38393 all at 10 mM) blunted the cAMP increase induced by subsequent D1R agonist challenge by 40–60% (1 mM SKF-81297). In contrast, pretreatment with the non-catechol agonist PF-2334 did not diminish the subsequent elevation in cAMP by D1R agonist challenge. In vivo, after 72 hours of chronic treatment with a catechol agonist (A-77636), animals displayed near-zero contralateral rotational behavior. In contrast, non-catechol agonist (PF-2334) treated animals were still rotating at the 72-hour time point. The absence of rotational behavior under A-77636 was likely due to D1R tachyphylaxis since treatment with a D2 agonist caused a significant increase in the number of contralateral rotations. The persistent in vitro and in vivo pharmacodynamic response of PF-2334 supports limited receptor desensitization by non-catechol agonists and suggests durable D1R agonism by PF-2334. These data highlight the therapeutic potential of this novel class of compounds and warrants further investigation in relevant Alzheimer's disease animal models.

Alkalides are compounds possessing anionic alkali metals (Li−, Na−, K−, etc.). We have predicted a new class of inorganic alkalides by sandwiching alkali atoms between Li2F superalkali clusters. These FLi2–M–Li2F systems (M = Li, Na and K) are found to be stable in which M possesses anionic charge of −0.69e to −0.36e. The ionization potentials of these alkalides are lower than those of M and decrease with the increase in atomic number of M whereas their mean polarizabilities increase exceeding to 103 a.u. for M = K. Thus, superalkali clusters can be employed to design novel alkalides with interesting electronic properties.