N

RIMAs is the same as in the nonselective NCEs: increase of monoamines, near to the receptor, leads, after a number of intermediate steps, to activation of functional proteins in the cell. The control of therapy with MAO-A inhibitors is easier, because of their reversibility. Of the current RIMAs, only moclobemide has been shown to have mild to moderate effects in depression.41 The development of RIMAs, as antidepressants and with possible anti-Parkinson activity, has had limited success to date, and is constrained by the tyramine effect, since the amine can displace the inhibitor from its binding site on the enzyme. Therefore, the Holy Grail of RIMAs would be to inhibit both forms of the enzymes to get the full functional activities of the amine neurotransmitters, without inducing a tyramine effect or 'cheese reaction.' This was not possible until recently, with the development of the novel cholinesterase-brain-selective MAO-A/B inhibitor ladostigil (22), a carbamate derivative of the irreversible MAO-B inhibitor rasagiline. Ladostigil (22) is a brain-selective MAO-A and MAO-B inhibitor; even after 2 months of daily administration it has little or no effect on the enzyme in the intestinal tract and liver.43 Pharmacologically, it has a limited tyramine potentiation effect, similar to moclobemide, but it has the antidepressant, anti-Parkinson, and anti-Alzheimer activities of an MAO-A/B inhibitor in the respective animal models used to develop such NCEs. No clinical studies have been reported with this novel compound.

NMe2

Imipramine 23

NMe2

NMe2

Clomipramine 24

~NMe2 Amitryptiline 25

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