Dopamine, acetylation

Like silylation, acetylation is effective as a means to substitute exchangeable hydrogens in alcohols, phenols, and primary and secondary amines. The reagents used for acetylation are acid anhydrides such as acetic anhydride, propionic anhydride, or trifluoroacetic anhydride. The reaction temperatures vary between 50 and 150°C and the reaction time from 15 minutes to 2 hours. As for silylation, all traces of water must be avoided. As an example, dopamine acetylation by trifluoroacetic anhydride is presented in Figure 1.5. °... 

The neurotransmitter must be present in presynaptic nerve terminals and the precursors and enzymes necessary for its synthesis must be present in the neuron. For example, ACh is stored in vesicles specifically in cholinergic nerve terminals. It is synthesized from choline and acetyl-coenzyme A (acetyl-CoA) by the enzyme, choline acetyltransferase. Choline is taken up by a high affinity transporter specific to cholinergic nerve terminals. Choline uptake appears to be the rate-limiting step in ACh synthesis, and is regulated to keep pace with demands for the neurotransmitter. Dopamine [51 -61-6] (2) is synthesized from tyrosine by tyrosine hydroxylase, which converts tyrosine to L-dopa (3,4-dihydroxy-L-phenylalanine) (3), and dopa decarboxylase, which converts L-dopa to dopamine. 

Dopamine, a vasodilator, has been widely used for treatment of acute circulatory failure. However, since dopamine is rapidly metabolized when administered orally, its use has been limited to intravenous infusion. Murata et al., studied the bioavailability and the pharmacokinetics of orally administered dopamine (DA). The oral administration of DA to dogs resulted in an absolute bioavailability of approximately 3%. To minimize the extensive first-pass metabolism of DA, a dopamine prodrug, V-(/V-acetyl-l-mcLhionyl)-o,o-bis(cLhoxycarbonyl)dopamine (TA-870), was synthesized [28] (Fig. 6). Since DA is a substrate for both mono-... 

Tolu P, Masi F, Leggio B, Scheggi S, Tagliamonte A, De Montis MG and Gambarana C (2002). Effects of long-term acetyl-L-camitine administration in rats (I) Increased dopamine output in mesocorticolimbic areas and protection toward acute stress exposure. Neuropsychopharmacology, 27, 410 420. 

Membrane-associated receptors are linked to transducing proteins (like G-proteins) in the inner portion of the membrane. G-protein coupled receptor (GPCR) families comprise a major class of the receptors that are pharmacologically relevant, such as muscarinic acetyl choline receptors, adrenoceptors, dopamine receptors, serotonine, opiate, peptide hormone, purinerg receptors, and also sensory chemoreceptors. A large variety of subtypes are described in the pharmacological literature. 

G-protein coupled receptor family comprises most well-known cell surface receptors including the major drug targets, as previously stated. Early PAL results have been reviewed in several papers, and book chapters. For opiate, NMDA, sigma, benzodiazepine, GABA, acetyl choline, and adrenerg, serotonine receptors see [52,59,60], and for purinerg, histamine, and dopamine receptors see [61]. 

Fig. 9.8 Examples of rule-of-three compliant molecules that have biological activity better than 10 nM. Under each molecule, the following information is included molecule name, MW, ClogP, the biological activity type, value and target. Target names are as follows D3 and D4 - dopaminergic receptor types 2 and 3 AChE and BChE - acetyl- and butyryl-choline esterases PRa and PRb - progesterone receptor types A and B H] and H3, histamine receptor types 1 and 3 5-HT2a, 5-HT2b, 5-HT2c, 5-HT3, 5-HT4 - serotonin receptor subtypes 2A, 2B, 2C, and types 3 and 4 DAT, NET, 5-HTT - dopamine, norepinephrine and serotonin transporter proteins /X], /x.2, S, ki, ks - opioid receptor types mu-1, mu-2, delta, kappa-1 and kappa-3 5a-Rl and 5o -R2 - 5-alpha-reductase isozymes 1 and 2 Flt-1-fms-like tyrosine kinase receptor.

Anticipation of reward hope acetyl choline dopamine... 

Omission of expected reward failure to achieve goal disappointment despondence acetyl choline serotonin dopamine... 

Important functional interactions of the dopaminergic and other key neurochemical systems have also been demonstrated. Durkin et al., (1986) reported that dopamine in the septum inhibits acetylcholine release in the hippocampus, whilst destruction of the A-10 septal dopaminergic pathways in mice results in increased choline acetyltransferase (Yanai et al., 1993). Pharmacological reduction of nigral dopamine levels to 5% of normal in guinea pigs results in a marked increase (over 70%) in the spontaneous release of acetyl-... 

Fig. 6.9 Activation of nitrite by peroxydases (a) and (b) nitration of phenol derivatives (c) nitration of Y-acetyl-tryptophan amide (d) nitration of dopamine...

Substrates (p-octopamine, dopamine, or 5-hydroxytryptamine) were separated from their N-acetylated products on an Ultrasphere I.P. C18 column (4.6 mm x 250 mm, 5 pm). The mobile phase was comprised of 75 mAf monobasic sodium phosphate, 1 pAf EDTA, 0.35 mAf 1-octanesulfonate (sodium salt), 11% methanol, and 4% acetonitrile. Coulometric detection was used. Detection of p-octopamine and its N-acetylated product was achieved at a potential of +0.75 V, while dopamine, 5-hydroxytryptamine and their products were detected at +0.50 V. 

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