Dpi 201–106

Abstract

Considerable efforts have been devoted to the development of nonglycoside cardiotonics. The mechanisms of action of clinically studied new compounds involve stimulation of cardiac P-adrenoceptors, histamine H2-receptors, and adenylate cyclase activity as well as inhibition of cyclic adenosine monophosphate (CAMP)-phosphodiesterase (PDE) (4). These effects lead in time to an increase in intracellular CAMP, which is likely to be responsible for their positive inotropic action.The recently discovered drug DPI 201-106 is a novel positive inotropic nonglycoside. Its activity is CAMP-independent and involves synergistic sarcolemmal and intracellular mechanisms. The properties of DPI 201-106 are described in this chapter. CHEMISTRYThe chemical structure of DPI 201-106 together with its chemical name is presented in Fig. 1. Its formula is C29H30N402, and its molecular weight is 466.59. DPI 201-106 is a crystalline bright yellow powder. The racemic mixture as well as the two optical enantiomers are soluble in N-methyl-2-pyrrolidone in acidic environment. PHARMACOLOGYIn Vitro Positive Inotropic Activity DPI 201-106 was found to increase the force of contraction in driven left atria from guinea pigs or rats (28); in papillary muscles from guinea pigs (3,28), rats (6,7), cats (28), rabbits (22,28), and dogs (30,31); and in rabbit (28) and hamster (21) hearts perfused according to Langendorff; but not in frog ventricles (7). The positive inotropic effect was concentration-dependent between lop7 and 3 X low6 M and reached the maximum within 2 hr. In most animal species the effects were not reversible upon extensive washing (3,28). The positive inotropic potency and efficacy of DPI 201-106 in rabbit papillary muscles were equal to that of ouabain 173