Cicletanine

Abstract

Cicletanine hydrochloride is a new antihypertensive molecule synthetized and studied in our laboratory. Its chemical structure is uncommon for an antihypertensive molecule; it is characterized by the presence of a furopyridine group. Cicletanine is, therefore, a member of a new family of compounds with primarily antihypertensive properties, although some of the furopyridine derivatives have also antiallergic and antiinflammatory effects.The mechanism by which cicletanine lowers blood pressure has not been definitively established, although it appears to differ from that of other classes of antihypertensive drugs. Cicletanine acts on vascular smooth muscle by increasing prostacyclin synthesis and by interacting either directly with cytosolic Ca2+ pools or indirectly through various agents capable of mobilizing intracellular Ca ' ' , e.g., histamine.Studies in animals and humans demonstrated that the antihypertensive effect of cicletanine is clearly dissociable from its renal effect, which can be seen only at highdose levels of the drug.Clinical trials have confirmed the efficacy and safety of cicletanine in the treatment of hypertension, both as monotherapy or in combination with other antihypertensive drugs. CHEMISTRYCicletanine was synthetized by Esanu et al. (9) in the research laboratories of Institute Henri Beaufour, Le Plessis-Robinson (France). It was selected from a large number of furopyridines for its specific antihypertensive activity and very low, if any, toxicity. The chemical structure of cicletanine ( HCl) : (-+ ) 3-(4-chloropheny1)-1,3dihydro-7-hydroxy-6-methyl furo[3,Cc]pyridine is shown in Fig. 1. Its chemical synthesis from 2-,2,8-trimethyl-5-formyl pyrido [ 4,3-el 1,3-dioxine has been described (9). Cicletanine HC1 has a molecular weight of 298.2. It is not soluble in 166 CICLE TANINE 167 water, but soluble in ethanol and dimethyl sulfoxide. It is a white crystalline powder with a melting point of 2 19-228°C. PHARMACOLOGY Effect on Blood PressureThe activity of cicletanine on blood pressure was evaluated in anesthetized normotensive rats and dogs and in several models of hypertensive rats: desoxycorticosterone acetate, spontaneously ( SH ) and stroke-prone spontaneously ( SH-SP) hypertensive rats and rats with stress-induced hypertension.In the anesthetized normotensive rat, cicletanine, administered orally at 100 and 300 mg/kg, did not affect either mean blood pressure or heart rate. The blood pressure effects of epinephrine, norepinephrine, acetylcholine, isoproterenol, or serotonin were not altered by pretreatment with cicletanine.The effect of intravenously injected cicletanine on the main hemodynamic cardiovascular parameters-systolic and diastolic aortic pressure, heart rate, aortic blood flow, coronary (circumflex artery) and femoral arterial blood flow-were studied in anesthetized normotensive dog. At doses higher than 5 mg/kg i.v., cicletanine produced only a slight and transient bradycardia, a minor reduction of systolic arterial pressure, and a brief decrease in diastolic pressure. F...

Modulation by low sodium intake of glomerular response to cicletanine and atrial natriuretic factor

“…Cicletanine (3‐(4‐chlorophenyl)‐1,3‐dihydro‐7‐hydroxy‐6‐methylfuro‐[3,4‐c] pyridine) is a novel agent that has been shown to possess vasorelaxant, natriuretic and diuretic properties in preclinical and clinical studies (Chabrier et al , 1988; Koltai et al , 1990). The mechanism(s) by which cicletanine (CIC) induces these biological effects has not been definitely established.…”

Prostacyclin and Hypertension

“…This effect was demonstrated only for higher doses (100 mg and over) and was usually accompanied by a marked stimulation of renal prostacycIin synthesis [98,99] . 48) [30]. 47).…”

“…46). However, it could be regarded as the natural consequence of prostacyclin stimulation [30,82,89] since prostacyclin can transfer free intracytosolic calcium into the calcium store of the cell via an elevation of the cellular cAMP content [140,302]. 45).…”

“…x increase in urine volume [30] 50 mg/day develops slowly and only attains its maximum after some 3 months, the remaining constant for up to over 2 years (Fig. 49) [99].…”

Effects of the antihypertensive agent, cicletanine, on noradrenaline release and vasoconstriction in perfused mesenteric artery of SHR

“…The antihypertensive agent cicletanine (CIC), a furopyridine derivative, exhibits several pharmacological actions on vascular vessels including activation of prostacyclin synthesis (Dorian et al , 1984; 1988; Calder et al , 1992a,b), histamine H 1 ‐receptor blockade (Schoeffter et al , 1987; Schoeffter & Godfraind, 1988), α 1 ‐adrenoceptor blockade (Chabrier et al , 1988), calcium channel blockade (Noack & Deitmer, 1993), opening of potassium channels (Koltai et al , 1990), inhibition of guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) phosphodiesterase (Silver et al , 1990; 1991), and direct relaxation of vascular smooth muscle (Auguet et al , 1988). The mechanism underlying the antihypertensive action of CIC is complex and not fully understood.…”