Chemistry:AH-1058
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| Formula | C30H28N2O3 |
| Molar mass | 464.565 g·mol−1 |
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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]
Medical 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][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]
Mode of action
The calcium blocking activity of AH-1058 can decrease ventricular contractility, heart rate, and conductance through the atrioventricular node.[1][3][7] 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.[8] 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).[7]
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 "Effects of AH-1058, a new antiarrhythmic drug, on experimental arrhythmias and cardiac membrane currents". Journal of Cardiovascular Pharmacology 33 (4): 625–32. April 1999. doi:10.1097/00005344-199904000-00016. PMID 10218734.
- ↑ "On the ionic mechanism of cyproheptadine-induced bradycardia in a rabbit sinoatrial node preparation". European Journal of Pharmacology 139 (3): 307–13. July 1987. doi:10.1016/0014-2999(87)90588-7. PMID 3666007.
- ↑ 3.0 3.1 3.2 3.3 3.4 "Electrophysiological and cardiohemodynamic effects of AH-1058, a new type calcium channel blocker, assessed by the in vivo canine model". Japanese Journal of Pharmacology 83 (2): 107–12. June 2000. doi:10.1254/jjp.83.107. PMID 10928322.
- ↑ "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. February 2001. doi:10.1016/s0014-2999(01)00740-3. PMID 11173068.
- ↑ 5.0 5.1 5.2 5.3 "AH-1058: a novel cardioselective Ca2+ channel blocker". Cardiovascular Drug Reviews 19 (4): 279–96. 2001. doi:10.1111/j.1527-3466.2001.tb00071.x. PMID 11830748.
- ↑ "Beta-blockers in hypertension". The American Journal of Cardiology 106 (12): 1819–25. December 2010. doi:10.1016/j.amjcard.2010.08.023. PMID 21126627.
- ↑ 7.0 7.1 7.2 7.3 "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 35 (5): 741–8. May 2000. doi:10.1097/00005344-200005000-00010. PMID 10813376.
- ↑ 8.0 8.1 8.2 8.3 "Utilization of telemetry system to assess the cardiovascular profile of AH-1058, a new cardioselective Ca2+ channel blocker, in conscious dogs". Japanese Journal of Pharmacology 85 (3): 331–4. March 2001. doi:10.1254/jjp.85.331. PMID 11325028.
- ↑ "Cardiac Ca(2+) channel-blocking effects of the cyproheptadine derivative AH-1058 in isolated guinea pig cardiomyocytes". Journal of Pharmacological Sciences 91 (2): 163–6. February 2003. doi:10.1254/jphs.91.163. PMID 12686762.
- ↑ "Calcium channel antagonistic effects of AH-1058, a novel antiarrhythmic drug, on guinea-pig myocardium". Research Communications in Molecular Pathology and Pharmacology 104 (1): 13–21. 1999. PMID 10604274.
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