Legal status
Legal status
  • Investigational
  • 1-[(E)-3-(3-Methoxy-2-nitrophenyl)prop-2-enyl]-4-(2-tricyclo[,8]pentadeca-1(15),3,5,7,9,11,13-heptaenylidene)piperidine
CAS Number
PubChem CID
Chemical and physical data
Molar mass464.565 g·mol−1
3D model (JSmol)
  • COC1=CC=CC(=C1[N+](=O)[O-])/C=C/CN2CCC(=C3C4=CC=CC=C4C=CC5=CC=CC=C53)CC2

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]


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]


  1. ^ a b c d e f g h i Takahara A, Uneyama H, Sasaki N, Ueda H, Dohmoto H, Shoji M, Hara Y, Nakaya H, Yoshimoto R (April 1999). "Effects of AH-1058, a new antiarrhythmic drug, on experimental arrhythmias and cardiac membrane currents". Journal of Cardiovascular Pharmacology. 33 (4): 625–32. doi:10.1097/00005344-199904000-00016. PMID 10218734.
  2. ^ 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. PMID 3666007.
  3. ^ a b c d e Takahara A, Sugiyama A, Dohmoto H, Yoshimoto R, Hashimoto K (June 2000). "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. doi:10.1254/jjp.83.107. PMID 10928322.
  4. ^ 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. PMID 11173068.
  5. ^ a b c d Takahara 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. PMID 11830748.
  6. ^ Ram CV (December 2010). "Beta-blockers in hypertension". The American Journal of Cardiology. 106 (12): 1819–25. doi:10.1016/j.amjcard.2010.08.023. PMID 21126627.
  7. ^ a b c d Takahara A, Sugiyama A, Dohmoto H, Yoshimoto R, Hashimoto K (May 2000). "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. doi:10.1097/00005344-200005000-00010. PMID 10813376.
  8. ^ a b c d Takahara A, Dohmoto H, Yoshimoto R, Sugiyama A, Hashimoto K (March 2001). "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. doi:10.1254/jjp.85.331. PMID 11325028.
  9. ^ Dohmoto H, Takahara A, Uneyama H, Yoshimoto R (February 2003). "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. doi:10.1254/jphs.91.163. PMID 12686762.
  10. ^ Tanaka H, Ichikawa T, Matsui S, Okazaki K, Masumiya H, Kawanishi T, Shigenobu K (1999). "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. PMID 10604274.