Concentration-effect relationships with FM 24: a new long acting beta-adrenergic receptor antagonist.

FM 24, 1-(2-exo-bicyclo[2,2,1] hept-2-tl phenoxy-3[(1-methyl/ethyl) amino]-2-propanol is a new β-adrenoceptor antagonist. The drug-receptor complex dissociates very slowly probably because of the rigidity of the norbornyl ring (Le Fur 1978). Five healthy male volunteers were given single oral doses of placebo, 20, 40, 80, 160 and 320 mg of FM 24. Two hours later a sub-maximal exercise test was carried out with measurement of heart rate and blood pressure and a blood sample was taken for measurement of the plasma concentration of FM 24. Progressive inhibition of exercise tachycardia was observed, related approximately linearly to the log concentration of the drug. At the 320 mg dose a high degree of inhibition of exercise tachycardia occurred with a maximum heart rate of 115 beats min. Five healthy volunteers were then given a single oral dose of 80 mg and 320 mg of FM 24 on separate occasions. Blood samples were taken and submaximal exercise tests were carried out before and at 2, 6, 12, 24, 36, 60, 108 and 168 h after the dose. The plasma concentration fell rapidly during the first 24 h and by that time was less than 10% of the peak value. The degree of inhibition of submaximal exercise tachycardia changed little during the first 24 h after the dose and thereafter declined at a rate which varied in different subjects. The main interest of the study lies in the difference in the concentration-effect relationship 2 h after doses of 20-320 mg and over 7 days after 80 mg or 320 mg doses. At 2 h there was an approximately linear relationship between log FM 24 concentration and inhibition of exercise tachycardia. In the 7 day study the inhibition of exercise tachycardia was on a plateau for the 6-24 h period. During this time the plasma concentration fell rapidly. The data are consistent with a prolonged duration of action due to a slow dissociation of the drug receptor complex, although an active metabolite of FM 24 cannot be excluded. The plateau of effect during the 6-24 h period is of particular interest. One possible explanation is that it represents the turnover time of the cardiac β-adrenoceptors.