Selective inhibitors of biosynthesis of aminergic neurotransmitters

Abstract

ALTHOUGH the enzymatic decarboxylation of amino acids is of substantial importance to biochemistry¹, there are few inhibitors of the decarboxylase enzymes which combine activity with selectivity. Several of the amines formed by in vivo decarboxylation of amino acids (biogenic amines) have key roles in physiology. The neurotransmitters dopamine, 5-hydroxytryptamine, histamine and γ-aminobutyric acid result from such enzymatic decarboxylation; dopamine in turn serves as the precursor of noradrenaline². The involvement of catecholamines in peripheral and central control of blood pressure has been the subject of many investigations; for example, elevated catecholamine levels were found in some of the 27 brain regions investigated in spontaneously hypertensive rats. Specifically, elevated noradrenaline and dopamine levels were found in regions implicated in the control of arterial blood pressure³. A widely reported biochemical theory of schizophrenia suggests disturbance of the dopaminergic system as the causative factor.⁴ Elevated histamine levels are believed to be involved in such diseases as allergy, hypersensitivity, gastric ulcer and inflammation⁵. Ornithine decarboxylase is also an important target for inhibition, as it is the initial enzyme in the biosynthesis of polyamines and increased levels of the latter have been associated with rapid cell division, including tumour growth⁶. Thus, selective inhibitors of these key enzymes could be of help in elucidating the complexities of neurophysiology and neurochemistry, as well as of service in medicine by correcting pathological levels of these agonists. We report here examples of the transformation of amino acids (C) into the corresponding substituted 3-fluoro-alanines (B), resulting in potent time-dependent decarboxylase inactivators (Table 1). In addition, we have prepared the fluoromethyl derivatives (D) corresponding to some of the amine products of these decarboxylases and find them also to be inactivators (Table 1).