Alpha-methyldopamine

Midha, K.K Hubbard, J.W. Bailey, K. and Cooper, J.K. Alpha-methyldopamine, a key intermediate in the metabolic disposition of... 

Easton N, Fry J, O Shea E, Watkins A, Kingston S, et al. 2003. Synthesis, in vitro formation, and behavioural effects of glutathione regioisomers of alpha-methyldopamine with relevance to MDA and MDMA (ecstasy). Brain Res 987 144-154. 

A topographical model has been proposed to explain why (E)-2-(3,4-dihydroxyphenyl)cyclopropylamine, 1, and alpha-methyldopamine (AMDA) are inactive in the renal vascular dopamine (DA) receptor system. In this model a steric protrusion (S2) resides approximately lX above the generalized plane of the receptor and acts to impede interaction with molecules such as 1 and AMDA which possess additional bulk in this region. Recent developments in DA structure-activity relationships offer further support for the existence of the S2 site. 

The close structural similarity of the semirigid conformational analogue 1 to the trans-rotamer of dopamine (DA) was noted almost ten years ago (1,2). The synthesis of 1 has been described more recently and its pharmacological profile determined (3-6) to be similar to alpha-methyldopamine (AMDA) which is inactive as a dopaminergic agent. 

Methyidopa should probably be avoided in patients with parkinsonism, because in theory the production of alpha-methyldopamine can worsen the disease, and there have indeed been reports of exacerbation (3). 

Hoffman, A.R. Rama-Sastry, B.V. and Axelrod, J. Formation of alpha- methyldopamine ("catecholamphetamine") from p-hydroxyamphetamine by rat brain microsomes. Pharmacology 19 256-260, 1979. 

The release of prolactin from the adenohypophysis is a centrally mediated event involving the dopaminergic neurons. Stimulation of these neurons blocks prolactin production, whereas blockade of dopaminergic function causes lactation. Chlorpromazine, which blocks dopamine receptors, reserpine, which depletes dopamine stores, and alpha-methyldopa, which forms a false transmitter such as alpha-methyldopamine, are all able to cause inappropriate lactation in a nonpregnant woman. 

The catecholamine-synthesizing enzymes are not only able to synthesize dopamine and norepinephrine from a physiologically occurring substrate such as L-dopa but also from exogenous substrates such as alpha-methyldopa, which is converted to alpha-methyldopamine and in turn to alpha-methylnorepinephrine. Alpha-methyldopamine and alpha-methylnorepinephrine are called false transmitters and, in general (except for alpha-methylnorepinephrine), are weaker agoifists (see Figure 37). 

Methyldopa (l -pathway directly parallels the synthesis of norepinephrine from dopa illustrated in Figure 6-5. Alpha-methylnorepinephrine is stored in adrenergic nerve vesicles, where it stoichiometrically replaces norepinephrine, and is released by nerve stimulation to interact with postsynaptic adrenoceptors. Flowever, this replacement of norepinephrine by a false transmitter in peripheral neurons is not responsible for methyldopa s antihypertensive effect, because the a-methylnorepinephrine released is an effective agonist at the cx adrenoceptors that mediate peripheral sympathetic constriction of arterioles and venules. In fact, methyldopa s antihypertensive action appears to be due to stimulation of central a adrenoceptors by a-methylnorepinephrine or a-methyldopamine. 

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