Objective: As a key member of the transient receptor potential (TRP) superfamily, TRP canonical 3 (TRPC3) regulates calcium homeostasis and contributes to neuronal excitability. Ablation of TRPC3 lessens pilocarpine-induced seizures in mice, suggesting that TRPC3 inhibition might represent a novel antiseizure strategy. Among current TRPC3 inhibitors, pyrazole 3 (Pyr3) is most selective and potent. However, Pyr3 only provides limited benefits in pilocarpine-treated mice, likely due to its low metabolic stability and potential toxicity. We recently reported a modified pyrazole compound 20 (or JW-65) that has improved stability and safety. The objective of this study was to explore the effects of TRPC3 inhibition by our current lead compound JW-65 on seizure susceptibility. Methods:We first examined the pharmacokinetic properties including plasma half-life and brain to plasma ratio of JW-65 after systemic administration in mice.We then investigated the effects of TRPC3 inhibition by JW-65 on behavioral and electrographic seizures in mice treated with pilocarpine. To ensure our findings are not model specific, we assessed the susceptibility of JW-65-treated mice to pentylenetetrazole (PTZ)-induced seizures with phenytoin as a comparator.Results: JW-65 showed adequate half-life and brain penetration in mice, justifying its use for central nervous system conditions. Systemic treatment with JW-65 before pilocarpine injection in mice markedly impaired the initiation of behavioral seizures. This antiseizure action was recapitulated when JW-65 was administered after pilocarpine-induced behavioral seizures were well established and was confirmed by time-locked electroencephalographic monitoring and synchronized video. Moreover, JW-65-treated mice showed substantially decreased susceptibility to PTZ-induced seizures in a dose-dependent manner.Significance: These results suggest that pharmacological inhibition of the TRPC3 channels by our novel compound JW-65 might represent a new antiseizure strategy engaging a previously undrugged mechanism of action. Hence, this
A highly efficient and atom economical one‐pot annulation strategy for novel tetrahydrothiopyrano[3,4‐b]indoles is presented. This protocol involves a Bi(OTf)3 catalyzed tandem Friedel–Crafts alkylation and intramolecular thia‐Michael addition reactions to furnish target molecules in an efficient manner. The method works effectively on substrates with unprotected indoles and also it is successfully employed to make tetrahydrothiepino[3,4‐b]indoles. The scaffolds synthesized are diverse and first of the kind. The reaction is practically simple with broad substrate scope and vast functional group compatibility.
A full account on the first total synthesis of a chroman meroterpenoid, (−)-phomoarcherin C, has been described. Key synthetic transformations include phenyl boronic acid-mediated 6π-electrocyclization reaction, a stereospecific hydrogenation driven by thermodynamic conformational stability of the product, and regioselective formylation. The strategy employed is considerably short, is atom-economical, and can open the doors to provide access to various other natural products of the same kind.
ID 14268 Poster Board 314Aberrant calcium signaling has intimate associations with multiple diseases. Upregulation of transient receptor potential canonical 3 (TRPC3), which is an ion channel that essentially mediates calcium influx, drives the progression of neurodegenerative diseases. We previously designed JW-65, a selective TRPC3 inhibitor with a favorable safety profile and good metabolic stability. However, JW-65 has moderate potency (IC 50 = 330 nM) and selectivity for TRPC3 inhibition. Here we report a synthetic JW-65 analog, 60a, with significantly improved potency and selectivity. 60a is a potent TRPC3 inhibitor (IC 50 = 90 nM) with no detectable inhibitory effect on the close homologs TRPC6/7, highlighting 60a as the first truly selective TRPC3 inhibitor. In vitro evaluations of 60a reveal its rescuing abilities on neuronal damage. In vivo studies indicate 60a is a promising candidate for further development as a potential AD therapy with a novel mechanism of action.
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