Bedeutung der N- und α-Methylierung für die Affinität von Brenzcatechinaminen zu den adrenergischen Receptoren

Summary

1. N-methylation of dopamine yielding epinine means potentiation of the α-adrenergic pressor action in the cat. It is only N-methylation which renders dopamine to a direct acting β-sympathomimetic amine: the positive inotropic effect of epinine on the isolated electrically driven guinea pig auricle remained uninfluenced by pretreatment of the animals with reserpine, whereas the dose-response curve of dopamine was shifted to the right.

The blood pressure lowering effect of epinine after phenoxybenzamine was—in contrast to that of dopamine—abolished by pronethalol.—N-methylation of noradrenaline doubled the affinity for the β-receptors of the heart.

2. Also by α-methylation dopamine gains affinity to the adrenergic β-receptors (heart and vessels): d-α-methyldopamine, an exclusively directly acting catecholamine, had a 40 times stronger inotropic action than dopamine on reserpinized auricles; the action of l-α-methyldopamine, a mainly indirectly acting amine, was only 4 times stronger than dopamine.

α-methylnoradrenaline, although having the same inotropic activity as noradrenaline, had a 10 times stronger depressor action than noradrenaline in the cat pretreated with phenoxybenzamine.

By α-methylation, the α-adrenergic pressor effect of dopamine as well as that of noradrenaline was enhanced only in the range of lower doses since the dose-response curves of the α-methylated compounds were generally less steep than those of the non-methylated catecholamines, indicating a lower “intrinsic activity” of the α-methylated derivatives.

3. The N- and α-methylated catecholamines α-methylepinine and α-methyladrenaline resp. were blood pressure lowering agents per se, because both methylgroups additively enhanced the affinity to the vascular β-receptors. α-methylepinine was the most potent β-sympathomimetic on the heart in the “dopamine series” (dopamine < d-α-methyldopamine ≈ epinine < dl-α-methylepinine). However, in the “noradrenaline series” the twofold methylated compound α-methyladrenaline had the lowest positive inotropic action (d(−)-adrenaline > d(−)-noradrenaline ≈ (−)erythro-α-methylnoradrenaline > (−) erythro-α-methyladrenaline).

4. From the results the following conclusions are drawn: The N- as well as the α-methyl-group exerts and “+I-effect” on the ammonium group. Thereby, protonation will be increased which leads to an enhanced affinity of the resp. catecholamine to the adrenergic α- and β-receptor. Since the α-CH₃ group—dependant upon its steric configuration—also causes a steric hindrance at the receptor site, the increase in affinity due to the +I-effect is partially neutralized. By that the lower intrinsic affinity of the α-methylated compounds as indicated by the different slope of their pressor dose-response curves, is also readily explained. Furtheron it is intelligible why α-methylation enhanced the β-adrenergic activity in the less potent “dopamine series” (preponderance of the “+I-effect”), whereas it lowered the affinity to the cardiac β-receptors in the “noradrenaline series” (preponderance of the steric hindrance).

5. Although α-methyladrenaline was the least potent β-sympathomimetic of the “noradrenaline series” in the guinea pig heart, it was the most potent compound in lowering the cat's blood pressure. Therefore, it seems to be questionable whether the cardiac and the vascular β-receptors and/or the mechanisms by which they induce the pharmacodynamic actions are identical.