The purpose of this theoretical study was to investigate the molecular features of some structurally unusual calcium antagonists with experimentally proved affinity to the diltiazem-binding site at L-type calcium channels. Therefore, sterical and electronic characteristics of cis-/trans-diclofurime, the verapamil-like derivatives McN-5691 and McN-6186 as well as the natural products papaverine, laudanosine, antioquine and tetrandrine were compared with the pharmacophoric requirements detected for classical diltiazem-like derivatives. This yielded a common pharmacophore model for all of these compounds. Based on this model, one single negative molecular electrostatic potential induced by the free electron pairs of the oxime oxygen of trans-diclofurime was detected that might be responsible for the stronger effects compared to the cis isomer. Furthermore, the dual diltiazem- and verapamil-like features of McN-5691 (and McN-6186) as well as the distinct pharmacophoric assignment of the laudanosine enantiomers may be interpreted on a molecular level. Finally, the crucial partial structure of the bis-benzylisoquinoline derivatives antioquine and tetrandrine being responsible for the calcium antagonistic effects could be revealed by superposition on the most active benzothiazepinone derivative 8-methoxydiltiazem. The results obtained for these unusual diltiazem mimics are discussed taking into consideration earlier findings for classical diltiazem-like derivatives.

01 Jan 1991·General Pharmacology: The Vascular System

Effects of Ca2+ channel ligands on [3H]QNB binding at m1 and m3 muscarinic receptors

Article

Author: Triggle, David J. ; Kwon, Yong Wha

1. The effects of Ca2+ channel ligands on [3H]QNB binding in m1- or m3-transfected Chinese hamster ovary (CHO) cells have been studied. 2. The IC50 values of Ca2+ channel ligands for the inhibition of [3H]QNB binding were between 10(-6) and 10(-4) M and the rank order of potency was HOE 166 greater than McN 6186 greater than nicardipine greater than tiamdipine greater than verapamil greater than diltiazem greater than Bay K 8644 greater than nifedipine at m1 and m3 receptors. 3. The results indicate that Ca2+ channel ligands employed in this experiment do not distinguish subtypes of muscarinic receptors.

01 May 1990·Journal of Cardiovascular PharmacologyQ4 · MEDICINE

Effects of the Novel Coronary Selective Calcium Channel Blocker, McN-6186, on Cardiocirculatory Dynamics Coronary Vascular Resistance, and Cardiac Output Distribution in Normal, Conscious Rats

Q4 · MEDICINE

Article

Author: Carson, John R. ; Brannan, Melvin D. ; Stranieri, Maria T. ; Gill, Alan ; Flaim, Stephen F.

The purpose of this study was to characterize the cardiocirculatory effects of the novel calcium channel blocker, McN-6186 (McN), normal, conscious rats. Animals were instrumented under halothane anesthesia for right atrial, left ventricular, arterial, and venous pressure recordings. The radioactive microsphere technique was used to measure regional blood flow (RBF) and cardiac output (CO) before (control) and during intravenous (i.v.) infusion of either McN at three doses (0.03, 0.1, 0.3 mg/kg) or vehicle at an equal infusion rate (0.0408 ml/min). Nifedipine (NIF) was also studied at three similar blood pressure (BP)-lowering doses (0.025, 0.150, and 0.375 mg/kg). The predominant effect of McN in conscious rats was to cause coronary vasodilation. The coronary vasodilator potency of McN was similar to NIF (ED25, McN = 0.03 mg/kg, NIF = 0.025 mg/kg). Neither McN nor NIF significantly changed systemic vascular resistance (SVR) over their respective coronary vasodilator dose ranges, suggesting that both compounds are selective coronary vasodilators. The doses of McN and NIF that reduced mean arterial pressure (MAP) by 25% (ED25) were similar (McN = 0.3 mg/kg, NIF = 0.375 mg/kg). At equal BP-lowering doses, McN increased coronary flow by 145% versus 110% for NIF. McN did not have major effects on other regions of the peripheral circulation. There was, however, some vasodilator activity in the renal and cerebral vascular beds. Because McN reduced coronary vascular resistance at a dose lower than that required to reduce resistance in other vascular beds, this compound appears to be a selective coronary vasodilator and may have therapeutic efficacy as an antianginal agent.

100 Deals associated with McN-6186

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Indication	Highest Phase	Country/Location	Organization	Date
Heart Failure	Discovery	US	McNeil Technologies, Inc.	-

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