Comparison of mibefradil and derivative NNC 55-0396 effects on behavior, cytochrome P450 activity, and tremor in mouse models of essential tremor.
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.
Research Service, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California 90073 U.S.A; Department of Neurobiology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095 USA.
Arnulfo
A
Quesada
Molecular Toxicology Interdepartmental Program, Department of Pathology and Laboratory Medicine, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095 USA.
Peter H
PH
Bui
Departments of Anesthesiology and Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261 USA.
Gregg E
GE
Homanics
Molecular Toxicology Interdepartmental Program, Department of Pathology and Laboratory Medicine, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095 USA.
Oliver
O
Hankinson
Neurology Service, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA 90073 USA.
Adrian
A
Handforth
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001562:Benzimidazoles / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D003521:Cyclopropanes / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004195:Disease Models, Animal; D020329:Essential Tremor / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D017353:Gene Deletion; D006246:Harmaline / Q000378:metabolism; D006900:Hydroxylation / Q000187:drug effects; D008745:Methylation / Q000187:drug effects; D020748:Mibefradil / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D009281:Naphthalenes / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D011963:Receptors, GABA-A / Q000172:deficiency / Q000235:genetics; D013329:Structure-Activity Relationship; D013739:Testosterone / Q000378:metabolism
D001562:Benzimidazoles; D003521:Cyclopropanes; D009281:Naphthalenes; D011963:Receptors, GABA-A; C484287:NNC 55-0396; D020748:Mibefradil; D013739:Testosterone; D003577:Cytochrome P-450 Enzyme System; D006246:Harmaline
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