MM-11

Calcium channel blockers have become important tools in the treatment of cardiovascular disorders and other diseases. Hybridization of well established calcium antagonist subclasses was an attempt to optimize their pharmacological profile. The intension of this study was to investigate the electrophysiological properties of MM 10 and MM 11 two newly synthesized compounds structurally closely related to KT-362 (5-[3-[[2-(3,4-dimethoxyphenyl)ethyl]amino]-1-oxopropyl]-2,3,4,5-tetrahydro-1,5-benzothiazepine fumarate) in various isolated guinea pig heart muscle preparations by means of the conventional intracellular microelectrode tech-nique. MM 10 (2,3-dihydro-1-[N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methylaminoacetyl]-1H-pyrido[2,3-b][1,4]thiazine fumarate) and MM 11 (2,3-dihydro-1-[N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methylaminopropionyl]-1H-pyrido[2,3-b][1,4]thiazine fumarate) exerted very similar effects though the action of MM 11 was more pronounced. Whereas action potential amplitude and maximum upstroke velocity (V(max)) in papillary muscle, left atria and spontaneously beating Purkinje fibers was not affected by the compounds in a concentration range from 3 to 30 micromol/l, action potential duration at 90% time to repolarization was significantly prolonged in a concentration-dependent manner. Action potential duration at 20% time to repolarization was decreased in spontaneously beating Purkinje fibers and remained unchanged in papillary muscles and left atria. In sinoatrial nodes both compounds reduced rate of activity, action potential amplitude, maximum upstroke velocity and slope of slow diastolic depolarization while time to repolarization was prolonged. In 3 out of 6 experiments with spontaneously beating Purkinje fibers, MM 11 (30 micromol/l) led to the occurrence of early afterdepolarizations with a take off potential between -50 and -60 mV. All observed effects were completely reversible during washout with drug-free physiological salt solution. From these results it was concluded that both compounds in addition to their calcium antagonistic properties might depress repolarizing potassium currents. In contrast to the mother compound KT-362 they do not seem to affect the fast sodium inward current. Replacement of the benzothiazepine nucleus by a pyridothiazine structure may weaken or even eliminate sodium channel blocking ability. Shortening of the side chain might result in a general loss in activity.

The effects of newly synthesized pyridothiazepines MM 4 (1-[N-[2-(3,4-dimethoxy-phenyl)ethyl]-N-methylaminoacetyl]-1,2,3,4 -tetrahydro-pyrido[2,3-b][1,4]thiazepine fumarate), MM 6 (1-[N-[2-(3,4-dimethoxyphenyl)-ethyl]-N-methylaminopropionyl]-1,2, 3,4-tetrahydro-pyrido[2,3-b][1,4]thiazepine fumarate) and the novel pyridothiazines MM 10 (2,3-dihydro-1-[N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methylaminoacetyl+ ++]-1H-pyrido[2,3-b][1,4]thiazine fumarate) and MM 11 (2,3-dihydro-1-[N-[2-(3,4-dimethoxy-phenyl)ethyl]-N-methylaminopropio nyl]-1H-pyrido[2,3-b][1,4]thiazine fumarate) on the contractility of isolated papillary muscles and aortic preparations of guinea pigs were studied using isometric contraction force measurements. The EC50 values for the negative inotropic effect were 27 micromol/l (MM 4), 19 micromol/l (MM 6), 32 micromol/l (MM 10) and 24 micromol/l (MM 11). In K+-precontracted aortic rings ([K+]o 60 mmol/l), the compounds induced relaxation with EC50 values of 27 micromol/l (MM 4), 24 micromol/l (MM 6), 84 micromol/l (MM 10) and 68 micromol/l (MM 11). Pyridothiazepines as well as pyridothiazines (100 micromol/l) were able to depress norepinephrine bitartrate (NE 10 micromol/l)-induced contraction of aortic rings in a calcium-free solution. It was concluded that the investigated compounds exert calcium antagonistic properties in both cardiac and smooth muscle. This antagonistic effect might be due to the inhibition of transmembrane calcium influx and/or intracellular calcium release.