Highly potent irreversible inhibitors of aromatic l -amino acid decarboxylase

Current awareness series Highly potent irreversible inhibitors of aromatic L-amino acid decarboxylase The enzyme aromatic Lamino acid decarboxylase (EC. 4.1.1.26; AADC) cat alyses the formation of dopamine from L-dopa and S-HT from LS-hydroxytlyptophan. Its activity is normally greatly in excess of that of either tyrosine or tryp tophan hydroxylase; decarboxylation is. therefore, not the rate-limiting step in the monoamine biosynthetic pathways. Although inhibitors of AADC have been known for many yearP. none. with the possible exception of decaborane’, has proven potent enough 10 render the decarboxylase step r&-limiting and to inhibit endogenous monoamine biosynthesisas a consequence. This situation has recently changed with the development of several new inhibitors of AADC by scientists at Merck Sharp and Dohme” and Merrell Dowa,‘. These compounds,exemplified by Dt_-n-monofluoromethyldopa (MFMD: Fig. I ). are all close structuralanaloguesof the natural substrate,t.-dopaJ,S.and have in common a novel, irreversible mode of inhibitory action, remarkable selectivity and, above all, potency more than adequate to ensure inhibition of monoamine biosynIhesis”. MFMD is an enzyme-activated enzyme inhibitor. Thus, the compound per w does not directly inhibit AADC. Rather it is accepted by the enzyme as a substrateand decarboxylated to yield a highly reactive intermrdiale which alkylates the enzyme and inactivates il irreversiblyJ. It soon became apparentthat MFMD had properties radically different from the AADC inhibitors hitherto described. Biochemical analysis disclosed an zxceg lional p0tenc.yas an Inhibitor of AADC in viva and. signiticantly. that essentially complete inhibition of the enzyme could be obtained?%.The result was depletion of the c;rtzchalamine neurorranstnittersand 5.HT in both the peripheral and central nervous syslems and associated funcrional impairmenP lo. The potential of such highly potent inhibitors of AADC as tools for the pharmacologisl are clear. FirsI. they offer an

allemative 10 (Fhydroxydopamme or rcserpine as a means of producing chemical sympathectomy. Unlike 6hydrnxjdopaminr. MFMD does not destroy the symparhcticneurone?,“‘; unlike reserpine. MFMD appears to spare both adrenal and extra-adrenal chromaffm tissue from depletion”. In rontrast to borh 6hydroxldop amine and reset-pine,subsrantialinhlbition of sympathetic function is obtained with minimal sensitizationof the innervated tis suey.“‘. A further feature of the chemical sympdthectomyobtained uith MfMD is its ready reversibility either in viva or in vitro by exposure of tissues to dopamine” “‘. Combining MFMD pretreatment with reversal of the peripheral monoamine deficit in this way provides a novel approach to the selective inhibition of central monoamincrgic function. Second. putent inhibitorsof AADC offer a unique approach to the measurement of monoamine nunover”. Following a single high dose of MFMD. both the accumuls tion of the precursor amino acid c~tf the decline in the amine concenlration can be measured to provide the rates of S-HT and catecholamine synthesis and catabolism in a single experiment”. The capacity of a single ~‘cposureto MfWD to inhibit rapidly. irrevcrcibl) anJ highly selectively the hynthexis oi endogenousmonoamines has implications for those working with systems in wluch ongoing synthesis may Jiston analyses based on an assumption of steady-state conditions. In a recent example. Muscholl and Spiral” have used XlFhlD to establish that the major factor invrfering N ith the sto’:hiometr) of neuronal noradrenahne and dopamine &h)drox~lasc release tilllowing depolarizing stimuh is the tltarrc~c) synthesisof noradrenaline.