Effect of the macrocyclic polyester 15-crown-5 on ionic permeability of excitable membranes

Abstract

The parmacology and biophysics of macrocyclic polyester complexones have been at the focus of attention of research workers in recent years [9, 16]. The use of these compounds as modulators of ionic permeability of excitable membranes is particularly interesting. It was shown in [16] that 15-crown-5 has a marked chronotropic and inotropic action on the isolated frog heart, which provides the basis for a search for new cardiotropic drugs in the macrocyclic polyester series.The aim of this investigation was to study the mechanism of action of 15-crown-5 on biological and model membranes. EXPERIMENTAL METHODThe strength and frequency of contraction of the isolated guinea pig atrium were recorded by means of a strain-gauge transducer, Topaz-2 amplifier, and N-3020-3 automatic writer.The velocity of contraction was estimated by means of a piezoelectric transducer. The signal from the transducer was recorded photographically from the oscilloscope screen. The refractory period of atrial contractions was determined by the method described previously [8]. Ionic currents of the electrically excitable membrane of isolated rat spinal ganglionic neurons were measured under intracellular dialysis and voltage clamp conditions by the method in [7]. The effect of 15-crown-5 on the surface potential of biomembranes was studied on a bimolecular lipid membrane (BLM) by a potentiodynamic method [i]. BLM was formed on the mouth of a small Teflon jar from a solution of phosphatidylcholine in decane (40 mg/ml). EXPERIMENTAL RESULTSPolyester 15-crown-5 in a concentration of 5-i0-~-i0 -3 M did not affect the force of contraction of the isolated rat heart but reduced the frequency of its contractions.A similar effect was observed on the isolated guinea pig atrium (Fig. i). The negative chronotropic action of the polyester on the atrium was combined with lengthening of the refractory period of its contractions (Fig. i) and a decrease in the velocity of the contractions.In a concentration of 10 -3 M it reduced the velocity by 48%.In the same concentrations 15-crown-5 did not affect the chronotropic reactions of the heart to acetylcholine and adrenalin and its action was unchanged in the presence of atropine and Inderal (propranolol).As a first approximation the action of 15-crown-5 on the heart of warm-blooded animals can thus be reduced to a change in the parameters of excitability of the sinuatrial node.Because of the high stability constant of complexes of 15-crown-5 with ions of the alkaline earth metals in water [Ii], it can be postulated that some of the effects of the compound described above on the atrium may be sensitive to Ca ++ concentration.In fact 15-crown-5, in a concentration of 2"10 -4 M, abolished the action of Ca ++ on the refractory period of contractions of the guinea pig atrium.Simple calculations show that the decrease in the Ca++ concentration in physiological saline on account of complex formation with 15-crown-5 did not exceed 5%. Judging from the relationship between the action of Ca++ and its *Deceased.

Design and synthesis of a new steroid-macrocyclic derivative with biological activity

“…1 Synthesis of pyrimidin-2-thione (3) or pyrimidin-2-one derivatives (4) using the threecomponent system (2-hydroxy-1-naphthaldehyde (2), acetophenone, and urea or thiourea) to form 3 or 4. i potassium hydroxide Fig. 2 Synthesis of OTBS-steroid-amino derivative (5 On the other hand, the following stage was achieved by the preparation of an ether group involved in the chemical structure of 7 (Fig. 4).…”

“…There are several studies which indicate that some macrocyclic derivatives exert a positive inotropic activity on the heart [3][4][5][6]. Nevertheless, the cellular site and molecular mechanism involved in their inotropic activity are very confusing; perhaps, this phenomenon is due to differences in the chemical structure of macrocyclic derivatives or to the different pharmacological approaches used.…”

“…Also, there is a study which shown the positive inotropic activity of the macrocyclic d-HP-DO3A in male Sprague-Dawley rats [4]. Additionally, other studies indicate that the macrocyclic polyester 15-crown-5 exerts a positive inotropic effect via calcium channels in isolated guinea pig atrium [5]. Contrary these experimental results, a study indicates that the macrocyclic xestospongin attenuates the positive inotropic effect by α-adrenergic stimulation in guinea pig papillary muscle [6].…”