Overview: Calmodulin and Calmodulin-Antagonists

High-Throughput Screening of TRPV1 Ligands in the Light of the Bioluminescence Resonance Energy Transfer Technique

“…Nine of the twelve compounds belonging to cluster E are composed of poly-cycle rings-containing molecules. Interestingly, Perhexilin maleate (#20) and Prenylamine Lactate (#32) that had been detected as inhibitors by intramolecular BRET probe in the primary screen are both Calmodulin antagonists (Caldirola et al, 1992), and have been confirmed as inhibitors of CAPS-induced TRPV1 activation by APC whatever the voltage used (Fig. 8 and Sup.…”

“…This prompted us to perform an in-depth analysis of the literature focusing on these clusters. Strikingly, we found that 12 of the 24 hits belonging to cluster E, G, and J are well-known calmodulin antagonists (Trifluopromazine (#01), Chlorpromazine (#03), Thioridazine (#04); Cyproheptadine (#05); Perphenazine (#06), Loperamide (#11), Clotrimazole (#18), Perhexiline maleate (#20), Quinacrine (#22), Fluphenazine (#23), Felodipine (#28), Prenylamine Lactate (#32)) (Rochette-Egly et al, 1982;Johnson and Wittenauer, 1983;Mannhold et al, 1987;Montero et al, 1991;Caldirola et al, 1992;Hegemann et al, 1993;Xin and Zhang, 1993;Oláh et al, 2007;Lübker and Seifert, 2015).…”

“…Nine out of the ten compounds belonging to cluster G are antipsychotropic drugs derived from phenothiazine (Triflupromazine (#01), Chlorpromazine (#03), Thioridazine (#04), Perphenazine (#06), Quinacrine (#22), fluphenazine (#23), Metixene (#30), Methotrimeprazine (#44), and Thiethylperazine maleate (#54)). Phenothiazines are among the most potent calmodulin inhibitors, especially when the phenothiazine derivative is substituted by a halogen (Rochette-Egly et al, 1982;Caldirola et al, 1992). The tenth compound of the cluster G, Cyproheptadine (#05), which is not a phenothiazine, has been described as a Calmodulin inhibitor in one study (Xin and Zhang, 1993) and is structurally related to Amitriptyline, a known Calmodulin inhibitor (Hugh Reynolds and Claxton, 1982).…”