Tryptamines serotonin agonist activity

Serotonin Agonists. Dysfunction of neurotransmission mediated by 5-hydroxy-tryptamine (5-HT serotonin) occurs in the basal ganglia of patients with PD, and excessive serotonergictransmission may contribute to dyskinesias associated with dopaminergic treatments (186). 5-HT receptors are expressed presynaptically on 5-HT terminals, where they limit serotonin release as autore-ceptors (187). Their activation should decrease 5-HT release and perhaps alleviate dopaminergic dyskinesias in PD (188). Because 5-HTia receptor stimulation can reverse par-... 

Numerous tryptamines bind with high affinity at 5-HTia receptors, but most are notoriously nonselective. One of the most selective 5-HTia receptor agonists is the aminotetralin derivative 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH DPAT), and its early discovery was significant in advancing an understanding of 5-HTia receptors. Furthermore, because the structure of 8-OH DPAT is similar to that of 5-HT (8-OH DPAT/serotonin), its activity indicated that an intact indole nucleus was not required for 5-HT ia actions. Although numerous 8-OH DPAT derivatives have been reported, none is used therapeutically because of low oral bioavailability. This has led to efforts to develop novel aminotetralins with greater oral availability. 

The prototype of this class is serotonin (5-HT) a potent but non-selective 5-HTjb agonist [6,2] (Table 2). The hydroxyl group at position C-5 is a prerequisite for high affinity. The unsubstituted analogue tryptamine is hardly active [7]. Replacement of the 5-hydroxy group by methoxy (5-MeOT) reduces aiffinity by two decades. 

As Eilbracht and coworkers [38] showed in numerous examples, the reaction cascade hydroformylation—(Fischer indolization) is a useful protocol for the synthesis of three-substituted indoles, including the essential amino acid tryptophan, the tissue hormone melatonin, and the neutrotransmitter serotonin (Figure 5.25). In addition, pharmacologically active tryptamine or homotryptamine derivatives, such as the marketed serotonin agonists sumatriptan, naratriptan, or zolmitriptan, or compounds that show a platelet aggregation inhibitory and antithrombotic effect (vintoperol) can be synthesized by such a protocol. Also active drug components for the treatment of schizophrenia (sertindole) can probably be produced by this approach [39]. It is estimated that the worldwide demand for such indole derivatives is about 20 000 mt/a [40]. 

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