AH-1058 is a lipophilic antiarrhythmic

calcium channel blocker Calcium channel blockers (CCB), calcium channel antagonists or calcium antagonists are a group of medications that disrupt the movement of calcium () through calcium channels. Calcium channel blockers are used as antihypertensive drugs, i.e., as ...

synthesized by the Pharmaceutical Research Laboratories of Ajinomoto Co., Inc in Kawasaki,

Japan Japan ( ja, 日本, or , and formally , ''Nihonkoku'') is an island country in East Asia. It is situated in the northwest Pacific Ocean, and is bordered on the west by the Sea of Japan, while extending from the Sea of Okhotsk in the north ...

. It is derived from cyproheptadine, a compound with known antiserotonic,

antihistaminic Antihistamines are drugs which treat allergic rhinitis, common cold, influenza, and other allergies. Typically, people take antihistamines as an inexpensive, generic (not patented) drug that can be bought without a prescription and provides re ...

and calcium channel blocking properties. The IUPAC name of AH-1058 is: 4-(5H-dibenzo ,dyclohepten-5-ylidene)-1- -3-(3-methoxy-2-nitro) phenyl-2-propenyliperidine hydrochloride.

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. Some proposed uses for AH-1058 include the treatment of angina pectoris,

stenosis A stenosis (from Ancient Greek στενός, "narrow") is an abnormal narrowing in a blood vessel or other tubular organ or structure such as foramina and canals. It is also sometimes called a stricture (as in urethral stricture). ''Stricture'' ...

of the outflow tract from obstructive

hypertrophic cardiomyopathy Hypertrophic cardiomyopathy (HCM, or HOCM when obstructive) is a condition in which the heart becomes thickened without an obvious cause. The parts of the heart most commonly affected are the interventricular septum and the ventricles. This r ...

and

ventricular arrhythmias Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adults ...

. 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 Energy consumption is the amount of energy used. Biology In the body, energy consumption is part of energy homeostasis. It derived from food energy. Energy consumption in the body is a product of the basal metabolic rate and the physical activity ...

. Studies have compared AH-1058 to widely used and clinically available drugs such as

verapamil Verapamil, sold under various trade names, is a calcium channel blocker medication used for the treatment of high blood pressure, angina (chest pain from not enough blood flow to the heart), and supraventricular tachycardia. It may also be used ...

(a Class IV antiarrhythmic drug) and atenolol (a beta blocker) 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 Vascular resistance is the resistance that must be overcome to push blood through the circulatory system and create flow. The resistance offered by the systemic circulation is known as the systemic vascular resistance (SVR) or may sometimes be cal ...

is an important advantage over atenolol and

, 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. AH-1058 studies have been limited to

in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...

and

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...

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.

Pharmacology

Mechanism of action

AH-1058 is a cardioselective L-type calcium channel blocker. AH-1058 binds to the same sites on the alpha-1 subunit of

L-type calcium channels The L-type calcium channel (also known as the dihydropyridine channel, or DHP channel) is part of the high-voltage activated family of voltage-dependent calcium channel. "L" stands for long-lasting referring to the length of activation. This c ...

phenylalkylamines Substituted phenethylamines (or simply phenethylamines) are a chemical class of organic compounds that are based upon the phenethylamine structure; the class is composed of all the derivative compounds of phenethylamine which can be formed by ...

(ex. verapamil) and

benzothiazepine Thiazepines are substituted thiepins, with a nitrogen replacing a carbon in the seven-membered heterocyclic compound. Depending on the location of the nitrogen, one distinguishes 1,3-thiazepine and 1,4-thiazepine. Benzothiazepines have a sing ...

s; both of which are well known calcium channel blockers. 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.

Mode of action

The calcium blocking activity of AH-1058 can decrease ventricular contractility, heart rate, and conductance through the atrioventricular node. In addition AH-1058 has been shown to decrease systolic blood pressure while minimally affecting total

and leaving

diastolic blood pressure Blood pressure (BP) is the pressure of circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term "blood pressure" r ...

unaffected. The order of the potency of the effects AH-1058 has on the

cardiovascular system The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...

is: ventricular contraction > coronary blood flow >> atrioventricular conduction > sinoatrial automaticity (level of sinoatrial self-activation).

References

{{Reflist, 30em Calcium channel blockers Antiarrhythmic agents Dibenzocycloheptenes