5-Methyl-6-phenyl-1,3,5,6-tetrahydro-3,6-methano-1,5-benzodiazocine-2,4- dione (BA 41899): Representative of a Novel Class of Purely Calcium-Sensitizing Agents

Abstract

BA 41899 (5-methyl-6-phenyl-1,3,5,6-tetrahydro-3,6-methano-1,5- benzodiazocine-2,4-dione, 6) is a structurally novel 1,5-benzodiazocine derivative and represents the prototype of a hitherto unknown class of positive inotropic Ca(2+)-sensitizing agents. It is completely devoid of phosphodiesterase (PDE) III inhibitory activity or any other known inotropic mechanism. BA 41899 (6) exhibits a pharmacological in vitro profile comprising Ca(2+)-sensitizing, positive inotropic, and negative chronotropic effects. CGP 48506 ((+)-6), the (+)-enantiomer of BA 41899 (6), enantiospecifically carries Ca2+ sensitization by up to a full pCa unit and a corresponding positive inotropic effect. Conversely, the negative chronotropic action resides in the corresponding (-)-enantiomer, CGP 48508 ((-)-6). All the effects are exerted in the low micromolar range. The positive inotropic action of CGP 48506 ((+)-6) is associated with a decelerating effect on contraction and, more prominently, relaxation dynamics in isolated guinea pig atria. In contrast to Ca(2+)-sensitizing PDE inhibitors, CGP 48506 ((+)-6) does not increase maximum Ca(2+)-activated force in myocardial skinned fibers.

From Vetiver to Patchouli: Discovery of a NewHigh‐Impact Spirocyclic Patchouli Odorant

“…To find out which one, we decided to make use of Enders's SAMP-/RAMP-hydrazone methodology, [19] which has also been used occasionally for the separation of racemic ketones or aldehydes by chromatography. [20] The (-)-(S)-1-amino-2-methoxymethylpyrrolidine auxiliary was introduced simply by refluxing 15 with SAMP in EtOH. The resulting hydrazones were separable by silica-gel FC, and 35 and 36 (Scheme 4) were isolated in 34 % and 39 % yield, respectively.…”

Pharmacological Profile of CGP 48506, A New Positive Inotropic Agent

“…Moreover, CGP 48506 did not bind significantly to PI-or aladrenoceptors or to histamine receptors (14). These findings suggest that CGP 48506 is not an agonist at the membrane receptors that mediate positive inotropic effects in the heart (Table 1).…”

“…Indeed, CGP 48506 but not CGP 48508 was an effective Ca2+ sensitizer in porcine right ventricular skinned fibers (EC,, = 10 FM; 14). The inotropically inactive enantiomer CGP 48508 did not exert Ca2+-sensitizing properties ( 14,20,3 I). These findings indicate that CGP 48506 possesses a specific Ca"-sensitizing action.…”

“…The positive inotropic effect of CGP 48506 was highly dependent on the rate of stimulation: only at low rates of stimulation was this effect detectable (14). At higher, more physiological rates CGP 48506 had only a transient positive inotropic effect (14). In isolated spontaneously beating guinea pig right atria, CGP 48508 exerted a negative chronotropic effect, whereas CGP 48506 had no effect on the rate of spontaneous contractions (14).…”

“…CGP 48506 had a concentration-dependent positive inotropic effect on isolated electrically driven guinea pig left atria (5,14,31). The effect was maximal at 30 p M CGP 48506 with an EC,, of -8 pM.…”