| Width: | 180 |
| Legal Status: | Investigational |
| Iupac Name: | 1-[(''E'')-3-(3-Methoxy-2-nitrophenyl)prop-2-enyl]-4-(2-tricyclo[9.4.0.03,8]pentadeca-1(15),3,5,7,9,11,13-heptaenylidene)piperidine |
| Cas Number: | 300347-11-9 |
| Cas Supplemental: | 228123-15-7 (HCl) |
| Pubchem: | 9804490 |
| Unii: | 2AH1DI0W9U |
| C: | 30 |
| H: | 28 |
| N: | 2 |
| O: | 3 |
| Smiles: | 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.[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]
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. Some proposed uses for AH-1058 include the treatment of angina pectoris, stenosis of the outflow tract from obstructive hypertrophic cardiomyopathy and ventricular arrhythmias.[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.
Studies have compared AH-1058 to widely used and clinically available drugs such as verapamil (a Class IV antiarrhythmic drug) and atenolol (a beta blocker)[5] 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. 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. Lastly AH-1058 displays a greater selectivity for cardiac tissue over verapamil and atenolol with the same level of potency as verapamil in vitro.[6] AH-1058 studies have been limited to in vitro and in vivo canine and guinea-pig models, with a greater potency displayed in vitro than in vivo. Along with decreased potency in vivo, blood levels do not correlate with AH-1058 activity.
AH-1058 is a cardioselective L-type calcium channel blocker.[7] 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.[8] 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. In addition AH-1058 appears to interact with multiple states of L-type calcium channels (i.e. resting and inactive) to suppress calcium currents. A minor effect on sodium channels at higher concentrations has also been seen, but these effects appear to vary between species.
The calcium blocking activity of AH-1058 can decrease ventricular contractility, heart rate, and conductance through the atrioventricular node.[9] 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.[10] 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).