AH-1058

AH-1058 is a lipophilic antiarrhythmic calcium channel blocker synthesized by the Pharmaceutical Research Laboratories of Ajinomoto Co., Inc in Kawasaki, Japan.[1] It is derived from cyproheptadine, a compound with known antiserotonic, antihistaminic and calcium channel blocking properties.[1][2] The IUPAC name of AH-1058 is: 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-[E-3-(3-methoxy-2-nitro) phenyl-2-propenyl]piperidine hydrochloride.[3]

Mechanism of Action

AH-1058 is a cardioselective L-type calcium channel blocker.[1][3][4] 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]

Effects

The calcium blocking activity of AH-1058 can decrease ventricular contractility, heart rate, and conductance through the atrioventricular node.[1][3][6] In addition AH-1058 has been shown to decrease systolic blood pressure while minimally affecting total peripheral vascular resistance and leaving diastolic blood pressure unaffected.[7] The order of the potency of the effects AH-1058 has on the cardiovascular system is: ventricular contraction > coronary blood flow >> atrioventricular conduction > sinoatrial automaticity (level of sinoatrial self-activation).[6]

Clinical Uses

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][8] 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][8]

Efficacy

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)[9] 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.[6][7] In addition, the minimal effects AH-1058 has on total peripheral vascular resistance is an important advantage over atenolol and verapamil, as these drugs an 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][10] 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.[6] Along with decreased potency in vivo, blood levels do not correlate with AH-1058 activity.[8]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 Takahara A, Uneyama H, Noriko U, et al. Effects of AH-1058, A new antiarrhythmic drug, on experimental arrhythmias and cardiac membrane currents. Journal of Cardiovascular Pharmacology 1999; vol 33:625-632
  2. ↑ Hiroshi K, Makoto S, Kazuhide O, et al. On the ionic mechanism of cyproheptadine-induced bradycardia in a rabbit sinoatrial node preparation. European Journal of Pharmacology 1987; vol 139:307-313
  3. ↑ 3.0 3.1 3.2 3.3 3.4 Takahara A, Sugiyama A, Dohmoto H, et al. Electrophysiological and cardiohemodynamic effects of AH-1058, a new type calicum channel blocker, assessed by the in vivo canine model. Japanese Journal of Pharmacology 2000; vol 83:107-112
  4. ↑ Tanaka H, Icikawa T, Matsui S, et al. Calcium channel antagonistic effects of AH-1058, a novel antiarrhythmic drug, on guinea-pig myocardium. Res Commun Mol Pathol Pharmacol 1999; vol 104:13-21
  5. ↑ 5.0 5.1 Takahara A, Sugiyama A, Yoshimoto R, et al. AH-1058: A novel cardioselective Ca2+ channel blocker. Cardiovascular Drug Reviews 2001; vol 19:279-296
  6. ↑ 6.0 6.1 6.2 6.3 Takahara A, Sugiyama A, Dohmoto H, et al. Comparison of cardiovascular effects of a new calcium channel blocker AH-1058 with those of verapamil assessed in blood-perfused canine heart preparations. Journal of Cardiovascular Pharmacology 2000; vol 35:741-748
  7. ↑ 7.0 7.1 Takahara A, Dohmoto H, Yoshimoto R, et al. Utilization of telemetry system to assess the cardiovascular profile of AH-1058, a new cardioselective calcium channel blocker, in conscious dogs. Japanese Journal of Pharmacology 2001; vol 85:331-334
  8. ↑ 8.0 8.1 8.2 8.3 8.4 Takahara A, Dohmoto H, Yoshimoto R, et al. Cardiovascular action of a cardioselective calcium channel blocker AH-1058 in conscious dogs assessed by telemetry. European Journal of Pharmacology 2001; vol 413: 101-108
  9. ↑ Ram CV. Beta blockers in hypertension. American Journal of Cardiology 2010; vol 106:1819-1825
  10. ↑ Dohmoto H, Takahara A, Uneyama H, et al. Cardiac calcium blocking effects of the cyproheptadine derivative AH-1058 in isolated guinea pig cardiomyocytes. Journal of Pharmacological Sciences 2003; vol 91:163-166