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This article describes the discovery of novel potent muscarinic receptor antagonists identified during a search for more active histamine H3 receptor (H3R) ligands. The idea was to replace the flexible seven methylene linker with a semirigid 1,4-cyclohexylene or p-phenylene substituted group of the previously described histamine H3R antagonists ADS1017 and ADS1020. These simple structural modifications of the histamine H3R antagonist led to the emergence of additional pharmacological effects, some of which unexpectedly showed strong antagonist potency at muscarinic receptors. This paper reports the routes of synthesis and pharmacological characterization of guanidine derivatives, a novel chemotype of muscarinic receptor antagonists binding to the human muscarinic M2 and M4 receptors (hM2R and hM4R, respectively) in nanomolar concentration ranges. The affinities of the newly synthesized ADS10227 (1-{4-{4-{[4-(phenoxymethyl)cyclohexyl]methyl}piperazin-1-yl}but-1-yl}-1-(benzyl)guanidine) at hM2R and hM4R were 2.8 nM and 5.1 nM, respectively.

Autism spectrum disorder (ASD) is a complex heterogeneous neurodevelopmental disorder characterized by social and communicative impairments, as well as repetitive and restricted behaviors (RRBs). With the limited effectiveness of current pharmacotherapies in treating repetitive behaviors, the present study determined the effects of acute systemic treatment of the novel multi-targeting ligand ST-2223, with incorporated histamine H3 receptor (H3R) and dopamine D2/D3 receptor affinity properties, on ASD-related RRBs in a male Black and Tan BRachyury (BTBR) mouse model of ASD. ST-2223 (2.5, 5, and 10 mg/kg, i.p.) significantly mitigated the increase in marble burying and self-grooming, and improved reduced spontaneous alternation in BTBR mice (all p &lt, 0.05). Similarly, reference drugs memantine (MEM, 5 mg/kg, i.p.) and aripiprazole (ARP, 1 mg/kg, i.p.), reversed abnormally high levels of several RRBs in BTBR (p &lt, 0.05). Moreover, ST-2223 palliated the disturbed anxiety levels observed in an open field test (all p &lt, 0.05), but did not restore the hyperactivity parameters, whereas MEM failed to restore mouse anxiety and hyperactivity. In addition, ST-2223 (5 mg/kg, i.p.) mitigated oxidative stress status by decreasing the elevated levels of malondialdehyde (MDA), and increasing the levels of decreased glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) in different brain parts of treated BTBR mice (all p &lt, 0.05). These preliminary in vivo findings demonstrate the ameliorative effects of ST-2223 on RRBs in a mouse model of ASD, suggesting its pharmacological prospective to rescue core ASD-related behaviors. Further confirmatory investigations on its effects on various brain neurotransmitters, e.g., dopamine and histamine, in different brain regions are still warranted to corroborate and expand these initial data.

The human phosphatidylinositol 4-phosphate 5-kinase type I α (hPIP5K1α) plays a major role in the PI3K/AKT/mTOR signaling pathway. As it has been shown before that hPIP5K1α is involved in the development of different types of cancer in particular prostate cancer, inhibitors of the enzyme might be a new option for the treatment of this disease. Here we report on the expression of hPIP5K1α on the surface of E. coli using Autodisplay. Autodisplay is defined as the surface display of a recombinant protein on a gramnegative bacterium by the autotransporter secretion pathway. After verification of surface expression, enzyme activity of whole cells displaying hPIP5K1α was determined by a capillary electrophoresis based assay. When using cells at an OD578 of 2.5, the artificial substrate phosphatidylinositol4-phosphate (PI(4)P) fluorescein was converted by a rate of 10.7 ± 0.2 fmol/min. Using this substrate inhibition of three pyranobenzoquinone type compounds was tested. The most active compound was 4-(2-amino-3-cyano-6-hydroxy-5,8-dioxo-7-undecyl-5,8-dihydro-4H-chromen-4-yl) benzoic acid with an IC50 value of 8.6 μM. Because until now, all attempts to purify hPIP5K1α failed, we suggest the use of whole cells of E. coli displaying the enzyme as a convenient tool for inhibitor identification.