Originator
Sensit,Thiemann,W. Germany,1974
Uses
Antianginal;Ca++ channel activator
Uses
Fendiline is an α2-adrenergic receptor antagonist (Kd = 2.6 μM) and an L-type calcium channel blocker (IC50 = 17 μM) well-known for its coronary vasodilator effects. Fendiline has recently been reported to inhibit K-Ras plasma membrane localization (IC50 = 9.64 μM), which prevents K-Ras signal transduction and blocks the proliferation of K-Ras-transformed tumor cells.
Manufacturing Process
21.13 grams of γ,γ-diphenyl-propylamine and 12.01 grams of acetophenone
are hydrogenated in 200 ml of methanol at 55°C and a pressure of 10
atmospheres in the presence of palladium charcoal. On filtration of the
catalyst the solution is concentrated and the remainder is distilled in vacuo at
a pressure of 0.3 Hg mm. The main distillate is collected at 206° to 210°C.
25.38 grams of N-[1'-phenylethyl-(1')]-1,1-diphenyl-propyl-(3)-amine are
obtained.
The product is dissolved in 134 ml of 96% ethanol whereupon 26.8 ml of
concentrated hydrochloric acid and 201 ml of water are added while cooling
with ice-water. The precipitate is filtered off and dried in vacuo at 100°C.
22.98 grams of N-[1'-phenylethyl)-(1')]-1,1-diphenyl-propyl-(3)-amine
hydrochloride are obtained. MP 200° to 201°C. On recrystallization from 285
ml of a 2:1 mixture of water and 96% ethanol the melting point remains
unchanged.
Therapeutic Function
Coronary vasodilator
Biological Activity
fendiline is an α2-adrenergic receptor antagonist and l-type calcium channel blocker [1,2].the α2 adrenergic receptor is a g protein-coupled receptor (gpcr). until now, three different α2-receptor subtypes have been identified: α2a, α2b, and α2c. the α2-adrenergic receptor exists in vascular prejunctional terminals and inhibits the release of norepinephrine in a form of negative feedback. the α2 adrenergic receptor agonists produce diverse responses, including analgesia, sedation, anxiolysis, and sympatholysis [3]. l-type calcium channels are responsible for the excitation-contraction coupling of skeletal, cardiac muscle, smooth, and for aldosterone secretion in endocrine cells of the adrenal cortex [4].fendiline inhibited the activity of l-type ca2+ channel blocker with the ic50 value of 17 μm [1]. fendiline inhibited the activity of α2-adrenergic receptor with the kd of 2.6 μm [2]. fendiline significantly reduced nanoclustering of k-ras and redistributed k-ras from the plasma membrane to the endoplasmic reticulum (er), golgi apparatus, endosomes, and cytosol. fendiline significantly inhibited signaling downstream of constitutively active k-ras and endogenous k-ras signaling in cells transformed by oncogenic h-ras. fendiline blocked the proliferation of pancreatic, colon, lung, and endometrial cancer cell lines expressing oncogenic mutant k-ras [5]. fendiline inhibited k-ras plasma membrane localization with an ic50 of 9.64 μm [5]. fendiline is an anti-anginal agent for the treatment of coronary heart disease. the anti-anginal and anti-ischaemic efficacy of fendiline has been proven in several placebo-controlled, double-blind trials [6].
References
[1] tripathi, o. ,schreibayer, w., and tritthart, h.a. fendiline inhibits l-type calcium channels in guinea-pig ventricular myocytes: a whole-cell patch-clamp study. british journal of pharmacology 108(4), 865-869 (1993).
[2] motulsky, h. j.,snavely, m.d.,hughes, r.j., et al. interaction of verapamil and other calcium channel blockers with α1- and α2-adrenergic receptors. circulation research 52(2), 226-231 (1983).
[3] kamibayashi t, maze m. clinical uses of α2-adrenergic agonists[j]. the journal of the american society of anesthesiologists, 2000, 93(5): 1345-1349.
[4] lipscombe d. l-type calcium channels[j]. 2002.
[5] van der hoeven d, cho k, ma x, et al. fendiline inhibits k-ras plasma membrane localization and blocks k-ras signal transmission[j]. molecular and cellular biology, 2013, 33(2): 237-251.
[6] bayer r, mannhold r. fendiline: a review of its basic pharmacological and clinical properties[j]. pharmatherapeutica, 1986, 5(2): 103-136.
