0 The antiserotoninergic activity at the serotonin receptor subtype 2 (5-HT2) of seven new 2-aminoethylbenzocyclanones was determined with respect to serotonin-induced contractions in rat aorta and compared with that of ketanserine ( p 4 = 8.87). Competitive antagonism was observed in six compounds (6.72 5 p 4 5 8.12). Three-dimensional structures and molecular electrostatic potential distributions of ketanserine and 2-aminoethylbenzocyclanones were analyzed. Several molecular features correlated with the rank of antiserotoninergic activity. In the case of the cyclanone fragment, the rank of activity was associated with the degree of planarity of the bicyclic system. The steric and electrostatic effects due to the loss of planarity were analyzed. In the case of the amino moiety, activity was associated with a particular spatial pattern defined by the amino nitrogen, the aromatic system, and molecular electrostatic potential minima generated by the oxygen atom. Figure 2-MEP maps of fragments X on a plane perpendicular to the aromatic ring. The plane contains the MEP minima generated by the carbonyl group vicinal to the ring: (A) X1; (B) X2; (C) X3; (D) X4.
The effects of the Na+/H+ exchange blocking drug diethylamiloride (DEA) on mechanical function have been studied in the rabbit isolated, arterially perfused interventricular septum. At concentrations of 10(-6)-10(-5) M, DEA induced a significant, dose-dependent, negative inotropic effect (a 54% decrease from control values at the highest concentration), which was slow to develop. After a 45 min washout, recovery was almost complete (95 +/- 3.4%). At concentrations greater than 5 x 10(-5) M, DEA induced a rapid and marked decrease in developed tension, associated with a progressive decrease in excitability and incomplete recovery. Resting tension was not significantly modified at any of the concentrations tested. At greater than 10(-6) M DEA enhanced significantly the transient negative inotropic effect of the brief intracellular acidosis induced by removal of NH4Cl perfusion, both by decreasing the minimal value of developed tension and by increasing the time required to produce this effect. These effects suggest that the dose-dependent DEA negative inotropic effect could be mediated by a progressive intracellular acidosis produced by inhibition of the Na+/H+ exchange system.
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