Elucidating the key signal transduction pathways essential for both antipsychotic efficacy and side-effect profiles is essential for developing safer and more effective therapies. Recent work has highlighted noncanonical modes of dopamine D 2 receptor (D 2 R) signaling via β-arrestins as being important for the therapeutic actions of both antipsychotic and antimanic agents. We thus sought to create unique D 2 R agonists that display signaling bias via β-arrestinergic signaling. Through a robust diversity-oriented modification of the scaffold represented by aripiprazole (1), we discovered UNC9975 (2), UNC0006 (3), and UNC9994 (4) as unprecedented β-arrestin-biased D 2 R ligands. These compounds also represent unprecedented β-arrestin-biased ligands for a G i -coupled G proteincoupled receptor (GPCR). Significantly, UNC9975, UNC0006, and UNC9994 are simultaneously antagonists of G i -regulated cAMP production and partial agonists for D 2 R/β-arrestin-2 interactions. Importantly, UNC9975 displayed potent antipsychotic-like activity without inducing motoric side effects in inbred C57BL/6 mice in vivo. Genetic deletion of β-arrestin-2 simultaneously attenuated the antipsychotic actions of UNC9975 and transformed it into a typical antipsychotic drug with a high propensity to induce catalepsy. Similarly, the antipsychotic-like activity displayed by UNC9994, an extremely β-arrestin-biased D 2 R agonist, in wild-type mice was completely abolished in β-arrestin-2 knockout mice. Taken together, our results suggest that β-arrestin signaling and recruitment can be simultaneously a significant contributor to antipsychotic efficacy and protective against motoric side effects. These functionally selective, β-arrestin-biased D 2 R ligands represent valuable chemical probes for further investigations of D 2 R signaling in health and disease.functional selectivity | ligand bias G protein-coupled receptors (GPCRs) signal not only via canonical pathways involving heterotrimeric large G proteins, but also via noncanonical G protein-independent interactions with other signaling proteins including, most prominently, β-arrestins (1-4). The process by which GPCR ligands differentially modulate canonical and noncanonical signal transduction pathways is a phenomenon known as "functional selectivity" (5, 6). Such functionally selective ligands preferentially engage either canonical or noncanonical GPCR pathways (7,8). Clearly, the discovery of ligands with discrete functional selectivity profiles will be extremely useful for elucidating the key signal transduction pathways essential for both the therapeutic actions and the side effects of drugs (6). Understanding which signaling pathways contribute to antipsychotic efficacy and side effects, for instance, will in turn enable the design of better antipsychotic drug candidates and, ultimately, lead to safer and more effective therapies for patients. However, only a small number of functionally selective GPCR ligands have been reported to date (5-9). In addition to the paucity of such ligands,...

Growing evidence suggests that protein lysine methyltransferases (PKMTs) and protein arginine methyltransferases (PRMTs) are associated with the development of various human diseases, including cancer, inflammation, and psychiatric disorders. Given the significant role of these proteins in human disease, efforts to discover selective small-molecule inhibitors of these enzymes are quickly gaining momentum. In this review, we focus on the recent progress in the discovery of selective PKMT and PRMT inhibitors. A future perspective on developing methyltransferase inhibitors is also offered.

An asymmetric Mannich reaction of phenylacetate thioesters and sulfonylimines using cinchona alkaloid-based amino (thio)urea catalysts is reported that employs proximity-assisted soft enolization. This approach to enolization is based on the cooperative action of a carbonylactivating hydrogen bonding (thio)urea moiety and an amine base contained within a single catalytic entity to facilitate intracomplex deprotonation. Significantly, this allows thioesters over a range of acidity to react efficiently, thereby opening the door to the development of a general mode of enolization-based organocatalysis of monocarboxylic acid derivatives. Soft enolization1,2 provides a mild and operationally simple approach to the deprotonation of certain types of monocarbonyl compounds. In contrast to hard enolization, wherein deprotonation is achieved irreversibly using a very strong base such as LDA, soft enolization occurs when a relatively weak amine base and a carbonyl activating component act in concert to effect reversible deprotonation. We have been investigating this mode of enolization with thioesters in direct carbon-carbon bond formation using Mg 2+ Lewis acids for carbonyl activation.2 Our inspiration for studying thioesters in this context stems from the way in which enolization occurs in the enzyme citrate synthase. 3 Thioester activation in citrate synthase is achieved by hydrogen bonding rather than Lewis-acid coordination (Scheme 1a). While a weaker form of carbonyl activation, it is sufficient to allow deprotonation by a weakly basic carboxylate group.4 This is likely due in large part to the proximity effects imparted to the system as a result of the close spatial arrangement of the ReV. Biophys. Chem. 1986, 15, 97-117. (4) The effect of hydrogen bonding on thioester acidity has been shown for acetyl-CoA dehydrogenase. See: Rudik, I.; Thorpe, C. Arch. Biochem. Biophys. 2001, 392, 341-348. (5) For accounts of proximity accelerated intramolecular transformations in general, see: (a) Menger, F. M.

[reaction: see text] Simple thioesters undergo direct aldol addition to aldehydes in the presence of MgBr(2).OEt(2) and i-Pr(2)NEt using untreated, reagent-grade CH(2)Cl(2) under atmospheric conditions. The reactions proceed extremely rapidly and in excellent yield.

A broadly applicable asymmetric synthetic strategy utilizing N-amino cyclic carbamate alkylation that provides access to the various stereochemical permutations of a common structural motif found in many polycyclic polyprenylated acylphloroglucinols is described. The utility of this methodology is demonstrated through the first asymmetric total synthesis of the antiviral agent (+)-clusianone.The polycyclic polyprenylated acylphloroglucinols (PPAPs) are a large and remarkably interesting class of natural products.1 Not only do these compounds exhibit wideranging biological activity but also they possess intriguing structures. Consequently, they have attracted considerable interest from the synthetic community, and a number of PPAPs have now been synthesized using a variety of innovative approaches.2 Despite the impressive advances resulting from this work, only a small number of syntheses have been conducted in an asymmetric fashion.2e,i,3 We recently described a new method for the asymmetric R-alkylation of ketones based on the use of chiral N-amino cyclic carbamate (ACC) auxiliaries. 4 In what follows, we outline a general asymmetric synthetic strategy utilizing this alkylation method that provides access to the various stereochemical permutations of a common structural motif found in many PPAPs. The synthetic potential of the resulting intermediates is highlighted by the first asymmetric total synthesis of the antiviral 5,6 agent (+)-clusianone (Scheme 1).(

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A facile and efficient four-component anti-selective direct aldol addition of thioester enolates has been developed that is fully compatible with enolizable aldehydes and able to be conducted using untreated reagent-grade CH2Cl2 open to the air. The thioester enolates are generated in situ via an acylation/conjugate addition sequence using commercially available PhSLi and acryloyl chloride, thus avoiding prior enolate formation while maintaining complete chemoselectivity. The organosulfur products are convertible into various polyketide-based structures.