AH-1058

Last updated
AH-1058
AH-1058.svg
Legal status
Legal status
  • Investigational
Identifiers
  • 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
PubChem CID
UNII
Chemical and physical data
Formula C30H28N2O3
Molar mass 464.565 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]

Contents

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]

Related Research Articles

An antianginal is a drug used in the treatment of angina pectoris, a symptom of ischaemic heart disease.

<span class="mw-page-title-main">Propranolol</span> Beta blocker drug

Propranolol, sold under the brand name Inderal among others, is a medication of the beta blocker class. It is used to treat high blood pressure, a number of types of irregular heart rate, thyrotoxicosis, capillary hemangiomas, performance anxiety, and essential tremors, as well to prevent migraine headaches, and to prevent further heart problems in those with angina or previous heart attacks. It can be taken by mouth or by injection into a vein. The formulation that is taken by mouth comes in short-acting and long-acting versions. Propranolol appears in the blood after 30 minutes and has a maximum effect between 60 and 90 minutes when taken by mouth.

<span class="mw-page-title-main">Verapamil</span> Calcium channel blocker medication

Verapamil, sold under various trade names, is a calcium channel blocker medication used for the treatment of high blood pressure, angina, and supraventricular tachycardia. It may also be used for the prevention of migraines and cluster headaches. It is given by mouth or by injection into a vein.

<span class="mw-page-title-main">Antiarrhythmic agent</span> Heart rhythm medication

Antiarrhythmic agents, also known as cardiac dysrhythmia medications, are a group of pharmaceuticals that are used to suppress abnormally fast rhythms (tachycardias), such as atrial fibrillation, supraventricular tachycardia and ventricular tachycardia.

<span class="mw-page-title-main">Quinidine</span> Antiarrythmic medication

Quinidine is a class IA antiarrhythmic agent used to treat heart rhythm disturbances. It is the enantiomer of antimalarial agent quinine, originally derived from the bark of the cinchona tree. The drug causes increased action potential duration, as well as a prolonged QT interval. As of 2019, its IV formulation is no longer being manufactured for use in the United States.

<span class="mw-page-title-main">Amlodipine</span> Dihydropyridine calcium channel blocker used to treat cardiovascular diseases

Amlodipine, sold under the brand name Norvasc among others, is a calcium channel blocker medication used to treat high blood pressure and coronary artery disease. It is taken by mouth.

<span class="mw-page-title-main">Diltiazem</span> Calcium channel blocker medication

Diltiazem, sold under the brand name Cardizem among others, is a calcium channel blocker medication used to treat high blood pressure, angina, and certain heart arrhythmias. It may also be used in hyperthyroidism if beta blockers cannot be used. It is taken by mouth or injection into a vein. When given by injection, effects typically begin within a few minutes and last a few hours.

<span class="mw-page-title-main">Sotalol</span> Medication

Sotalol, sold under the brand name Betapace among others, is a medication used to treat and prevent abnormal heart rhythms. It is only recommended in those with significant abnormal heart rhythms due to potentially serious side effects. Evidence does not support a decreased risk of death with long term use. It is taken by mouth or injection into a vein.

<span class="mw-page-title-main">Azimilide</span> Chemical compound

Azimilide is a class ΙΙΙ antiarrhythmic drug. The agents from this heterogeneous group have an effect on the repolarization, they prolong the duration of the action potential and the refractory period. Also they slow down the spontaneous discharge frequency of automatic pacemakers by depressing the slope of diastolic depolarization. They shift the threshold towards zero or hyperpolarize the membrane potential. Although each agent has its own properties and will have thus a different function.

<span class="mw-page-title-main">Ivabradine</span> Heart medication

Ivabradine, sold under the brand name Procoralan among others, is a medication, which is a funny current (If) inhibitor, used for the symptomatic management of heart-related chest pain and heart failure. Patients who qualify for use of Ivabradine for coronary heart failure are patients who have symptomatic heart failure, with reduced ejection volume, and heart rate at least 70 bpm, and the condition not able to be fully managed by beta blockers.

<span class="mw-page-title-main">Nebivolol</span> Chemical compound

Nebivolol is a beta blocker used to treat high blood pressure and heart failure. As with other β-blockers, it is generally a less preferred treatment for high blood pressure. It may be used by itself or with other blood pressure medication. It is taken by mouth.

<span class="mw-page-title-main">Prajmaline</span> Chemical compound

Prajmaline (Neo-gilurythmal) is a class Ia antiarrhythmic agent which has been available since the 1970s. Class Ia drugs increase the time one action potential lasts in the heart. Prajmaline is a semi-synthetic propyl derivative of ajmaline, with a higher bioavailability than its predecessor. It acts to stop arrhythmias of the heart through a frequency-dependent block of cardiac sodium channels.

<span class="mw-page-title-main">Adrenergic antagonist</span>

An adrenergic antagonist is a drug that inhibits the function of adrenergic receptors. There are five adrenergic receptors, which are divided into two groups. The first group of receptors are the beta (β) adrenergic receptors. There are β1, β2, and β3 receptors. The second group contains the alpha (α) adrenoreceptors. There are only α1 and α2 receptors. Adrenergic receptors are located near the heart, kidneys, lungs, and gastrointestinal tract. There are also α-adreno receptors that are located on vascular smooth muscle.

<span class="mw-page-title-main">Pilsicainide</span> Chemical compound

Pilsicainide (INN) is an antiarrhythmic agent. It is marketed in Japan as サンリズム (Sunrythm). It was developed by Suntory Holdings Limited and first released in 1991. The JAN applies to the hydrochloride salt, pilsicainide hydrochloride.

<span class="mw-page-title-main">Anipamil</span> Chemical compound

Anipamil is a calcium channel blocker, specifically of the phenylalkylamine type. This type is separate from its more common cousin Dihydropyridine. Anipamil is an analog of the more common drug verapamil, which is the most common type of phenylalkylamine style calcium channel blocker. Anipamil has been shown to be a more effective antiarrhythmic medication than verapamil because it does not cause hypertension as seen in verapamil. It is able to do this by bonding to the myocardium tighter than verapamil.

<span class="mw-page-title-main">BRL-32872</span> Chemical compound

BRL-32872 is an experimental drug candidate that provides a novel approach to the treatment of cardiac arrhythmia. Being a derivative of verapamil, it possesses the ability to inhibit Ca+2 membrane channels. Specific modifications in hydrogen bonding activity, nitrogen lone pair availability, and molecular flexibility allow BRL-32872 to inhibit K+ channels as well. As such, BRL-32872 is classified as both a class III (K+ blocking) and class IV (Ca+2 blocking) antiarrhythmic agent.

<span class="mw-page-title-main">Celivarone</span> Experimental drug being tested for use in pharmacological antiarrhythmic therapy

Celivarone is an experimental drug being tested for use in pharmacological antiarrhythmic therapy. Cardiac arrhythmia is any abnormality in the electrical activity of the heart. Arrhythmias range from mild to severe, sometimes causing symptoms like palpitations, dizziness, fainting, and even death. They can manifest as slow (bradycardia) or fast (tachycardia) heart rate, and may have a regular or irregular rhythm.

<span class="mw-page-title-main">F15845</span>

F15845 is a cardiac drug proposed to have beneficial effects for the treatment of angina pectoris, arrhythmias and ischemia by inhibiting the persistent sodium current. The drug, currently in phase II of clinical trials, targets the persistent sodium current with selectivity and produces minimal adverse effects in current experimental studies.

<span class="mw-page-title-main">Budiodarone</span> Chemical compound

Budiodarone (ATI-2042) is an antiarrhythmic agent and chemical analog of amiodarone that is currently being studied in clinical trials. Amiodarone is considered the most effective antiarrhythmic drug available, but its adverse side effects, including hepatic, pulmonary and thyroid toxicity as well as multiple drug interactions, are discouraging its use. Budiodarone only differs in structure from amiodarone through the presence of a sec-butyl acetate side chain at position 2 of the benzofuran moiety. This side chain allows for budiodarone to have a shorter half-life in the body than amiodarone which allows it to have a faster onset of action and metabolism while still maintaining similar electrophysiological activity. The faster metabolism of budiodarone allows for fewer adverse side effects than amiodarone principally due to decreased levels of toxicity in the body.

<span class="mw-page-title-main">Discovery and development of beta-blockers</span>

β adrenergic receptor antagonists were initially developed in the 1960s, for the treatment of angina pectoris but are now also used for hypertension, congestive heart failure and certain arrhythmias. In the 1950s, dichloroisoproterenol (DCI) was discovered to be a β-antagonist that blocked the effects of sympathomimetic amines on bronchodilation, uterine relaxation and heart stimulation. Although DCI had no clinical utility, a change in the compound did provide a clinical candidate, pronethalol, which was introduced in 1962.

References

  1. 1 2 3 4 5 6 7 8 9 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. 1 2 3 4 5 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. 1 2 3 4 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. 1 2 3 4 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. 1 2 3 4 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.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.