Title: Comparison of mibefradil and derivative NNC 55-0396 effects on behavior, cytochrome P450 activity, and tremor in mouse models of essential tremor.

Authors: Quesada, Arnulfo; Bui, Peter H; Homanics, Gregg E; Hankinson, Oliver; Handforth, Adrian

Published In Eur J Pharmacol, (2011 May 20)

Abstract: NNC 55-0396 [(1S,2S)-2-(2-(N-[(3-benzimidazol-2-yl)propyl]-N-methylamino)ethyl)-6-fluoro-1,2, 3,4-tetrahydro-1-isopropyl-2-naphtyl cyclopropanecarboxylate dihydrochloride], is a mibefradil derivative that retains potent in vitro T-type calcium channel antagonist efficacy. We compared the two compounds for behavioral toxicity, effects on cytochrome P450 activity, and efficacy against tremor in the γ-aminobutyric acid type A (GABAA) receptor subunit α1-null mouse, and the harmaline tremor model of essential tremor in wild-type mice. NNC 55-0396 was better tolerated than mibefradil in the horizontal wire test of sedation/motor function, with 3/6 failing at 300 and 30mg/kg respectively. To assess for a potential interaction with harmaline, mice were given the drugs, followed by harmaline or vehicle, and tested 30min later in the inverted wire grid test. Mibefradil exacerbated, whereas NNC 55-0396 ameliorated harmaline-induced test deficits. In mouse liver microsomes, NNC 55-0396 was a less potent inhibitor of harmaline O-demethylation than mibefradil (Ki: 0.95 and 0.29μM respectively), and also less potent at inhibiting testosterone 6-β-hydroxylation (Ki: 0.71 and 0.12μM respectively). In the GABAA α1-null model, NNC 55-0396 but not mibefradil, (each at 20mg/kg), suppressed tremor while NNC 55-0396 at 12.5mg/kg suppressed harmaline-induced tremor by half by 20-100min, whereas mibefradil at the same dose did not significantly affect tremor. In contrast to mibefradil, NNC 55-0396 is well tolerated and suppresses tremor, and exerts less cytochrome P450 inhibition. These results suggest potential clinical utility for NNC 55-0396 or similar derivatives as a T-type calcium antagonist.

PubMed ID: 21256842

MeSH Terms: Animals; Behavior, Animal/drug effects*; Benzimidazoles/chemistry*; Benzimidazoles/pharmacology*; Benzimidazoles/therapeutic use; Cyclopropanes/chemistry*; Cyclopropanes/pharmacology*; Cyclopropanes/therapeutic use; Cytochrome P-450 Enzyme System/metabolism*; Disease Models, Animal; Essential Tremor/drug therapy*; Essential Tremor/enzymology; Essential Tremor/metabolism; Gene Deletion; Harmaline/metabolism; Hydroxylation/drug effects; Methylation/drug effects; Mibefradil/chemistry*; Mibefradil/pharmacology*; Mibefradil/therapeutic use; Mice; Naphthalenes/chemistry*; Naphthalenes/pharmacology*; Naphthalenes/therapeutic use; Receptors, GABA-A/deficiency; Receptors, GABA-A/genetics; Structure-Activity Relationship; Testosterone/metabolism