Nicainoprol

Abstract

Nicainoprol is a newly synthesized antiarrhythmic agent, which can be categorized as a class I drug with slow kinetics; it has a minor, but significant class IV effect. Its chemical name is 8-(3-isopropylamino-2-hydroxy-propoxy)-I-nicotinoyl-1,2,3,4-tetrahydroquinoline (Fig. 1); other names are CAS-924 and RU-42924; its empirical formula is C,,H,,N,O,; the molecular weight is 370.2; it is a white powder; readily soluble in water at room temperature; pKa value of 9.0 (determined in Roussel-Uclaf) or 9.50 (27); and log P value of 1.03 (measured in our laboratory, see ref. 13) or 2.050 (27). IN VITRO EFFECTS Effects on Action Potential CharacteristicsElectrophysiologic studies on isolated dog Purkinje fibers and dog and guinea pig ventricular muscles indicated, that nicainoprol decreases the maximal upstroke velocity (Vmm) of the action potential in a concentration-dependent manner (3.3 to 100 pM) without changing the resting potential (6,13,20,28). In addition, the drug shortened the action potential duration (APD) and effective refractory period (ERP) of the dog Purkinje fiber (6,20). However, the effects of this drug on the APD of ventricular muscles are controversial (6,13,20,28). Nicainoprol produced statistically significant increases in the APD of dog and guinea pig ventricular muscles at concentrations of 3 and 10 pM, respectively (6,20). In other reports, the agent, at relatively low concentrations (1, 3.3, 5, and 10 pM), tended to increase the APD and ERP of the guinea pig ventricle, albeit the changes were not significant (13,28). In contrast, the drug, at higher concentrations (50 and 100 pM), significantly decreased the APD in guinea pig ventricular muscles ( 13,20).Based on these cellular electrophysiological effects, the most consistent and prominent effect of nicainoprol is considered to be a concentration-dependent reduction in the 6' -of action potentials, a measure of Na+ channel availability. Such depression of Vmm is a common property of class I type antiarrhythmic action as proposed by Vaughan Williams

Recent Syntheses of 1,2,3,4-Tetrahydroquinolines, 2,3-Dihydro-4(1H)-quinolinones and 4(1H)-Quinolinones using Domino Reactions

“…The 1,2,3,4-tetrahydroquinoline nucleus is a prevalent core structure in a myriad of synthetic pharmaceuticals as well. Nicainoprol ( 6 ) is an antiarrhythmic drug [28], oxamniquine ( 7 ) is a schistosomicide [29], and virantmycin ( 8 ) is an antiviral antibiotic that also possesses antifungal activity [30,31,32,33]. Additionally, compound 9 is being evaluated for use in the treatment of HIV [34], compound 10 is garnering attention as an agent to slow the onset of Alzheimer’s disease [35,36,37], and compound 11 is currently undergoing testing as an antimalarial agent [38].…”

Rhodium(III‐Catalyzed C8‐Selective C−H Alkenylation and Alkylation of 1, 2, 3, 4‐Tetrahydroquinolines with Styrenes and Allylic Alcohols

“…1,2,3,4‐Tetrahydroquinolines are important molecules because they constitute core structural units in a variety of biologically and pharmacologically active natural products and synthetic compounds [1] . For example, helquinoline is an antibiotic alkaloid from the North Sea bacterium Janibacter Limosus Hel 1, [2a] sumanirole acts as a high affinity D2 receptor agonist, [2b,c] ( S )‐flumequine is an antibacterial agent, [2d] nicainoprol [2e] is used as a novel antiarrhythmic agent and compound I has been identified as a glucocorticoid receptor ligand [2f] (Figure 1). Thus, considerable efforts have been made to the development of efficient methods for constructing these useful N‐heterocycles within the past several decades.…”

Synthesis of 4,4′-Disubstituted and Spiro-tetrahydroquinolines via Photochemical Cyclization of Acrylanilides and the First Synthesis of (±)-trans-Vabicaserin

“…1,2,3,4-Tetrahydroquinolines are important substructures in many biologically active molecules, and a vast number of synthetic methodologies have been established over the past decades. 1 The general motive can be found in marketed drugs like the anthelmintic oxamniquine 2 or the antiarrhythmic nicainoprol, 3 as well as a large number of natural products. 1 Despite the obvious relevance of the general substructure, a comparably limited number of reports in the literature show a precedence for 4,4′-dialkyl and even a smaller precedence for 4-spirocyclic tetrahydroquinolines.…”