Prenylamine (Segontin) is a

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 ...

of the

amphetamine Amphetamine (contracted from Alpha and beta carbon, alpha-methylphenethylamine, methylphenethylamine) is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, an ...

chemical class Chemical classification systems attempt to classify elements or compounds according to certain chemical functional or structural properties. Whereas the structural properties are largely intrinsic, functional properties and the derived classi ...

that was used as a

vasodilator Vasodilation, also known as vasorelaxation, is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. Blood vessel wal ...

in the treatment of

angina pectoris Angina, also known as angina pectoris, is chest pain or pressure, usually caused by insufficient blood flow to the heart muscle (myocardium). It is most commonly a symptom of coronary artery disease. Angina is typically the result of part ...

History

Prenylamine was introduced in the 1960s by German manufacturer Albert-Roussel pharma gmbh, which was acquired by

Hoechst AG Hoechst AG () was a German chemicals, later life sciences, company that became Aventis Deutschland after its merger with France's Rhône-Poulenc S.A. in 1999. With the new company's 2004 merger with Sanofi-Synthélabo, it became a subsidiar ...

in 1974 and which in turn became part of

Sanofi Aventis Sanofi S.A. is a French multinational pharmaceutical and healthcare company headquartered in Paris, France. The corporation was established in 1973 and merged with Synthélabo in 1999 to form Sanofi-Synthélabo. In 2004, Sanofi-Synthélabo merg ...

in 2005. It was withdrawn from market worldwide in 1988 because it caused QT interval prolongation and

torsades de pointes ''Torsades de pointes, torsade de pointes'' or ''torsades des pointes'' (TdP; also called ''torsades'') (, , translated as "twisting of peaks") is a specific type of abnormal heart rhythm that can lead to sudden cardiac death. It is a polymorph ...

, greatly increasing the risk of

sudden death Sudden Death or Sudden death may refer to: Medical * Cardiac arrest, also known as sudden cardiac death, natural death from cardiac causes * Sudden cardiac death of athletes * Sudden infant death syndrome * Sudden unexpected death in epilepsy *Su ...

. The cardiac side effects were not detected during clinical development, only becoming apparent after the drug was in wide use.

Mechanism of action

Prenylamine has two primary molecular targets in humans:

calmodulin Calmodulin (CaM) (an abbreviation for calcium-modulated protein) is a multifunctional intermediate calcium-binding messenger protein expressed in all Eukaryote, eukaryotic cells. It is an intracellular target of the Second messenger system, sec ...

and myosin light-chain kinase 2, found in skeletal and cardiac muscle. Pharmacologically, it decreases sympathetic stimulation on cardiac muscle, predominantly through partial depletion of

catecholamine A catecholamine (; abbreviated CA), most typically a 3,4-dihydroxyphenethylamine, is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine. Cate ...

s via

competitive inhibition Competitive inhibition is interruption of a chemistry, chemical pathway owing to one chemical substance inhibiting the effect of another by competing with it for molecular binding, binding or chemical bond, bonding. Any metabolism, metabolic or c ...

of reuptake by storage granules, leading to further depletion due to spontaneous leakage as a result of disturbance of equilibrium. This depletion mechanism is similar to that of

reserpine Reserpine is a drug that is used for the treatment of hypertension, high blood pressure, usually in combination with a thiazide diuretic or vasodilator. Large clinical trials have shown that combined treatment with reserpine plus a thiazide diur ...

because both agents target the same site on the storage granule; however, prenylamine shows a high affinity for cardiac tissue, while reserpine is more selective toward brain tissue. Prenylamine slows cardiac metabolism via calcium transport delay by blockade of magnesium-dependent calcium transport

ATPase ATPases (, Adenosine 5'-TriPhosphatase, adenylpyrophosphatase, ATP monophosphatase, triphosphatase, ATP hydrolase, adenosine triphosphatase) are a class of enzymes that catalyze the decomposition of ATP into ADP and a free phosphate ion or ...

. It demonstrates

beta blocker Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage abnormal heart rhythms ( arrhythmia), and to protect the heart from a second heart attack after a first heart attack ( secondary prevention ...

–like activity that results in reduction of heart rate but shows an opposing effect on tracheal tissue response.

References

{{Phenethylamines Vasodilators Substituted amphetamines Calcium channel blockers Norepinephrine-dopamine releasing agents