Serotonin Group

It is interesting to compare the structure of some alkaloids (Chapter 9) with these brain chemicals, dopamine, noradrenaline and serotonin. Many of the alkaloids are made from phenylalanine and tryptophan. For 

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Whilst the term biogenic amine strictly encompasses all amines of biological origin, for the purpose of this article it will be employed to refer to the catecholamine (dopamine, noradrenaline) and serotonin group of neurotransmitters. These neurotransmitters are generated from the amino acid precursors tyrosine and tryptophan, respectively, via the action of the tetrahydrobiopterin (BH4)-dependent tyrosine and tryptophan hydroxylases. Hydroxylation of the amino acid substrates leads to formation of 3,4-dihydroxy-l-phenylalanine ( -dopa) and 5-hydroxytryptophan, which are then decarboxylated via the pyridoxalphosphate-dependent aromatic amino acid decarboxylase (AADC) to yield dopamine and serotonin [4]. In noradrenergic neurones, dopamine is further metabolised to noradrenaline through the action of dopamine-jS-hydroxylase [1]. 

Figure 8.9 The serotonin group of important brain chemicals that also occur in some insect venoms...

Desipramine [50-47-5] (35) and nortriptyline [72-69-5] (36) are demethylated derivatives and principal metaboHtes of (32) and (33), respectively. Both compounds possess less sedative and stronger psychomotor effects than the tertiary amine counterparts, probably because tricycHcs containing secondary amine groups generally show greater selectivity for inhibiting the reuptake of norepinephrine compared with the reuptake of serotonin. Protriptyline [438-60-8] (37), a stmctural isomer of nortriptyline, is another important secondary amine that displays a similar clinical profile. 

Rimonabant (382) was also included in a clinical study to assess the safety and efficacy of four novel compounds for the treatment of schizophrenia and psychoaffective disorder [378]. The other compounds included in the trial were a neurokinin NK3 antagonist, a serotonin 2A/2C antagonist and a neurotensin NTSl antagonist. Halopeiidol and placebo groups were used as controls in the study. Sixty-nine patients received (382) (20 mg once per day), which failed to demonstrate efficacy in this trial. The reasons for the lack of efficacy may be due to inadequate dosing or an indication that CBi antagonism is not appropriate in the treatment of this condition. 

A number of non-hormonal therapies have been studied for symptomatic management of vasomotor symptoms, including antidepressants [e.g., selective serotonin reuptake inhibitors (SSRIs) and venlafaxine], herbal products (e.g., soy, black cohosh, and dong quai), and a group of miscellaneous agents (e.g., gabapentin, clonidine, and megestrol). The choice of therapy depends on the patient s concomitant disease states, such as depression and hypertension, and the risk for potential adverse effects. 

What was the scientific basis for these chemical-imbalance theories As I noted above, norepinephrine and serotonin are now known to be neurotransmitters - chemicals that transmit nerve impulses from one neuron to another. But in the 1950s knowledge of neurotransmission was sketchy at best. The presence of norepinephrine in the nervous system was not demonstrated until 1954, and evidence that dopamine functions as a neurotransmitter was not reported until 1958. As late as i960 the idea that neurotransmission is largely chemical in nature, though advocated by a group of largely British scientists, was not yet widely accepted.10... 

There is only one group of research subjects in whom rapid depletion of serotonin sometimes produces clinical depression. These are depressed patients in remission who are currently taking SSRIs. About half of these patients relapse when serotonin is depleted. Note that this only happens if they are still taking antidepressant medication. If they have stopped medication, depleting... 

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