Design and Synthesis of Novel GPR139 Agonists with Therapeutic Effects in Mouse Models of Social Interaction and Cognitive Impairment.

The GPR139 receptor is an orphan G-protein-coupled receptor (GPCR) mainly found in the central nervous system and is a potential therapeutic target for the treatment of schizophrenia and drug addiction. Guided by the reported structure of GPR139, we conducted medicinal chemistry optimizations of TAK-041, the GPR139 agonist in clinical trials. New compounds with three different core structures were designed and synthesized, and their activity at GPR139 was evaluated. Among them, compounds 15a (EC50 = 31.4 nM) and 20a (EC50 = 24.7 nM) showed potent agonist activity at GPR139 and good pharmacokinetic properties. In murine schizophrenia models, both compounds rescued the social interaction deficits observed in BALB/c mice. Compound 20a also alleviated cognitive deficits in mice with a pharmacologically induced model of schizophrenia. These findings further demonstrated the potential of GPR139 agonists in alleviating the negative symptoms and cognitive deficits of schizophrenia. Compound 20a is worth further evaluation as an antischizophrenia drug candidate.

Complete mitochondrial genome of the soybean leaffolder, Omiodes indicata (Lepidoptera: Pyraloidea: Crambidae), and phylogenetic analysis for Pyraloidea.

Complete mitochondrial genome (mitogenome) of the Omiodes indicata was sequenced and characterized. The circular mitogenome is 15,367bp long, including 13 protein-coding genes (PCGs), two ribosomal RNA genes (rRNAs), 22 transfer RNA genes (tRNAs), and an A+T-rich region. Nucleotide composition is highly biased toward A+T nucleotides (81.6%). All 13 PCGs initiate with canonical start codon (ATN), except for cox1 that initiates with CGA. All tRNAs have a typical clover-leaf structure, except for trnS1 (AGN) in which the base pairs of the dihydrouridine (DHU) arm are reduced. In O. indicata, the motifs "ATGATAA" and "ATACTAA" between atp8 and atp6, trnS2 and nad1, respectively, and the motifs "ATAG" and "ATTTA" in the A+T-rich region can be identified. Comparative phylogenetic analyses based on four datasets show that the dataset including all coding positions of 13 PCGs exhibit the highest informativeness in resolving higher phylogeny of Pyraloidea. Bayesian inference (BI) and maximum likelihood (ML) analyses yield generally well-supported phylogenetic relationships among the eleven pyraloid subfamilies involved. However, the relationships among the five subfamilies (Acentropinae, Crambinae, Glaphyriinae, Schoenobiinae and Scopariinae) in ML analysis are ambiguous, which might be resolved by ample sampling in future mitogenome-based phylogenetic studies.