Structure-activity relationship studies of three novel 4-aminopyridine K⁺ channel blockers

Abstract

4-Aminopyridine (4AP) is a specific blocker of voltage-gated potassium channels (K V 1 family) clinically approved for the symptomatic treatment of patients with multiple sclerosis (MS). It has recently been shown that [ 18 F]3F4AP, a radiofluorinated analog of 4AP, also binds to K V 1 channels and can be used as a PET tracer for the detection of demyelinated lesions in rodent models of MS. Here, we investigate three novel 4AP derivatives containing methyl (-CH 3 ), methoxy (-OCH 3 ) and trifluoromethyl (-CF 3 ) in the 3 position as potential candidates for PET imaging and/or therapy. We characterized the physicochemical properties of these compounds (pK a and logD) and analyzed their ability to block Shaker K + channel under different voltage and pH conditions. Our results demonstrate that all three derivatives are able to block voltage-gated potassium channels. Specifically, 3-methyl-4-aminopyridine (3Me4AP) was found to be approximately 7-fold more potent than 4AP, whereas the methoxy (3MeO4AP) and trifluoromethyl (3CF 3 4AP) containing compounds were about 3-to 4-fold less potent than 4AP, respectively. These results suggest that these novel derivatives are potential candidates for therapy and imaging.

Synthesis, characterization, potential antimicrobial, antioxidant, anticancer, DNA binding, and molecular docking activities and DFT on novel Co(II), Ni(II), VO(II), Cr(III), and La(III) Schiff base complexes

“…Moreover, they are broadly used in the symptomatic improvement of walking for the adults dealing with several variations of the disease. [30][31][32] The coordination chemistries of cobalt, 33 nickel, 34 oxovanadium, 35 chromium, [36] and lanthanum 37 are very ligand-dependent and are more important in medicine and biological systems, where the metal complexes that combine with DNA have gained a large concern as diagnostic agents and chemotherapeutic drugs, [38,39] where DNA is the essential intracellular objective of numerous anticancer medications in clinics, [40] and numerous anticancer drugs someway apply their antitumor impacts through binding to DNA, thereby impeding the replication of DNA and inhibiting the increase in tumor cells. [41,42] For the previous reasons, in this study, we focused on obtaining a new pyridine-based Schiff base along with its transition metal complexes of Co(II), Ni(II), VO(II), Cr(III), and La(III).…”

Metabolic Stability of the Demyelination Positron Emission Tomography Tracer [18F]3-Fluoro-4-Aminopyridine and Identification of Its Metabolites

“…After confirming the structure of the metabolites, we conducted further tests to determine their lipophilicity and brain permeability (Table 2). Our findings show that 5-hydroxy-3F4AP and 3F4AP N-oxide have octanol/water partition coefficient values at pH 7.4 of -0.465 and -1.204, respectively, while the value for 3F4AP is 0.414 (Rodriguez-Rangel et al 2020). This indicates that these metabolites preferentially partition in the aqueous layer and may have limited penetration of the blood-brain barrier (BBB) by passive diffusion, which was confirmed by their measured permeability rates using a PAMPA assay (Table 2).…”