AH-1058 displays characteristics of Class IV antiarrhythmics (L-type calcium channel blockers). Class I antiarrhythmic (sodium channel blocker) characteristics have also been seen, but the effect AH-1058 has on sodium channels is variable and unknown.[1] Some proposed uses for AH-1058 include the treatment of angina pectoris, stenosis of the outflow tract from obstructive hypertrophic cardiomyopathy and ventricular arrhythmias.[1][4] Treatment of these conditions (long term and short term) is possible due to the cardioselective nature of AH-1058 and the ability of AH-1058 to inhibit calcium channels and thus reduce cardiac contractility and energy consumption.[3][5]
Studies have compared AH-1058 to widely used and clinically available drugs such as verapamil (a Class IV antiarrhythmic drug)[1] and atenolol (a beta blocker)[6] to assess the efficacy of AH-1058. The effects of AH-1058 are slower to onset but longer-lasting than those of verapamil and atenolol.[7][5] In addition, the minimal effects AH-1058 has on total peripheral vascular resistance is an important advantage over atenolol and verapamil, as these drugs can be taken long term for disease management.[8] Lastly AH-1058 displays a greater selectivity for cardiac tissue over verapamil and atenolol with the same level of potency as verapamil in vitro.[8][9] AH-1058 studies have been limited to in vitro and in vivo canine and guinea-pig models,[3] with a greater potency displayed in vitro than in vivo.[7] Along with decreased potency in vivo, blood levels do not correlate with AH-1058 activity.[8]
Pharmacology
Mechanism of action
AH-1058 is a cardioselective L-type calcium channel blocker.[1][3][10] AH-1058 binds to the same sites on the alpha-1 subunit of L-type calcium channels as phenylalkylamines (ex. verapamil) and benzothiazepines; both of which are well known calcium channel blockers.[5] These sites on the alpha-1 subunit differ from the active site of the calcium channel, meaning AH-1058 binds L-type calcium channels allosterically to alter activity.[5] In addition AH-1058 appears to interact with multiple states of L-type calcium channels (i.e. resting and inactive) to suppress calcium currents.[1] A minor effect on sodium channels at higher concentrations has also been seen, but these effects appear to vary between species.[1]
^Kotake H, Saitoh M, Ogino K, Hirai S, Matsuoka S, Hasegawa J, Mashiba H (July 1987). "On the ionic mechanism of cyproheptadine-induced bradycardia in a rabbit sinoatrial node preparation". European Journal of Pharmacology. 139 (3): 307–13. doi:10.1016/0014-2999(87)90588-7. PMID3666007.
^Takahara A, Dohmoto H, Yoshimoto R, Sugiyama A, Hashimoto K (February 2001). "Cardiovascular action of a cardioselective Ca(2+)channel blocker AH-1058 in conscious dogs assessed by telemetry". European Journal of Pharmacology. 413 (1): 101–8. doi:10.1016/s0014-2999(01)00740-3. PMID11173068.
^ abcdTakahara A, Sugiyama A, Yoshimoto R, Hashimoto K (2001). "AH-1058: a novel cardioselective Ca2+ channel blocker". Cardiovascular Drug Reviews. 19 (4): 279–96. doi:10.1111/j.1527-3466.2001.tb00071.x. PMID11830748.