Design, synthesis and biological evaluation of novel multi-receptor ligands with potential application in schizophrenia therapeutics

Schizophrenia is a debilitating disease that affects approximately 1 % of the population worldwide. 5-HT7 antagonist, M4 agonist and low D2 antagonist 53 was shown to alleviate schizophrenia-like symptoms in vivo. However, this compound was later found to possess significant hERG liability (Figure 1). Figure 1: Proof of concept lead serominic amidine compound 53 at physiological pH. The human ether-à-go-go related gene (hERG) codes for a specific potassium ion channel in the heart and blockade of this channel by drugs can cause sudden death. The research programme focused mainly on reduction of hERG activity via pKa modulation by introduction of a linker with an electron-withdrawing group (EWG) in place of the basic (pKa = 12) amidine linker (Figure 2). Figure 2: pKa attenuation upon insertion of EWG. A number of analogous compounds with EWG linkers were synthesised and all compounds successfully reduced hERG activity compared to the lead amidine (53) (Figure 3). Figure 3: Schematic depicting hERG liability of each linker group compared to the amidine linker. The incorporation of an EWG linker has been discovered as a valuable strategy in reduction of hERG liability. Furthermore, a number of novel pathfinder compounds with promising multi-receptor profiles have been designed, synthesised and evaluated in radioligand binding assays. Further work may provide evidence for the utility of these multi-ligands as a new generation of antipsychotic therapies.

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