N-Aryl-2,6-dimethylbenzamides, a New Generation of Tocainide Analogues as Blockers of Skeletal Muscle Voltage-Gated Sodium Channels

Abstract

On the basis of a 3D-QSAR study, a new generation of tocainide analogues were designed and synthesized as voltage-gated skeletal muscle sodium channel blockers. Data obtained by screening new compounds by means of Hille-Campbell Vaseline gap voltage-clamp recordings showed that the elongation of the alkyl chain and the introduction of lipophilic and sterically hindered groups on the amino function enhance both potency and use-dependent block. The results provide additional indications about the structural requirement of pharmacophores for further increasing potency and state-dependent block and allowed us to identify a new tocainide analogue (6f) with a favorable pharmacodynamic profile to be proposed as a valid candidate for studies aimed at evaluating its usefulness in the treatment of myotonias.

Increased sodium channel use-dependent inhibition by a new potent analogue of tocainide greatly enhances in vivo antimyotonic activity

“…Through a series of previous SAR studies, we obtained two tocainide analogues, namely To040 and To042, showing greatly enhanced potency and use-dependent block of sodium currents recorded in frog skeletal muscle fibers (Carrieri et al., 2009, De Luca et al., 2004, De Luca et al., 2012, Muraglia et al., 2014, Talon et al., 2001). Here we show that these two compounds are also very potent blockers of human skeletal muscle voltage-gated sodium channels.…”

“…All drugs and chemicals were purchased from Sigma-Aldrich, whereas To040 and To042 were synthesized in our laboratories as salts, as previously described (Catalano et al., 2008, Muraglia et al., 2014). …”

“…In To040, the β-proline cycle was eliminated. In To042, the benzyl moiety was substituted for by a naphthalene group (Muraglia et al., 2014). …”

“…1), was 10 times more potent than tocainide in blocking human sodium channels and showed considerable analgesic activity in animal models of neuropathic pain (Ghelardini et al., 2010). Lately, on the basis of a 3D-QSAR study, new chemical maneuvers allowed to obtain two promising compounds 100 times more potent than tocainide, namely To040 and To042 (Carrieri et al., 2009, Muraglia et al., 2014) (Fig. 1).…”

Toward precision medicine in myotonic syndromes

“…These studies provided new insights into the relative role of pharmacophores for binding to crucial amino acid residues in Na v and suggest novel lead molecules for enhancing potency, use-dependence, and stereoselective behavior. These studies eventually result in the chemical optimization of a tocainide derivative, namely To042, exerting a very potent and use-dependent inhibition of Na v 1.4 channels [5]. Use-dependence is a cardinal characteristic of sodium channel blockers, allowing the drug to block channels in over-excited membranes that fire action potentials at high frequency, while preserving healthy tissue function.…”