5-HTiA-Serotonin agonists

Glennon, R.A. (1992) Concepts for the design of 5-HTiA serotonin agonists and antagonists. Drug Development Research, 26, 251-274. 

In addition to the aetions of MDMA and other derivatives at 5-HT2 serotonin reeeptors. some of the effeets on serotonergic systems could be mediated via S-HTja reeeptors, at whieh MDMA has a moderate affinity. Direct agonist effects at this site might eontribute to the mood-altering and calming effects of the drug, sinee similar effects have been reported for novel anxiolyties sueh as ipsaperone and buspirone, which interact with 5-HTia serotonin reeeptors. 

While much emphasis has been placed on alterations in noradrenergic neurotransmission, TCA drugs are not without effect on serotonin (5-HT) neurotransmission. Long-term studies with TCA drugs in animals have demonstrated postsynaptic supersensitivity to serotonin (5-HTia) receptor agonists at serotonin synapses, with an associated enhancement of serotonergic neurotransmission. The sensitization to 5-HTia agonists is mediated in part by an increase in the density of postsynaptic 5-HTia receptors. Enhancement of trans-... 

Trazodone is a triazolopyridine derivative, with relatively weak serotonin reuptake inhibition. Trazodone also has antagonist activity at 5-HTia and 5-HTic sites (Haria et ah, 1994). Trazodone s active metabolite, m-CPP, serves as a direct serotonin agonist. 

Buspirone is a nonbenzodiazepine anxiolytic serotonin 5-HTia partial agonist that may have a role in reducing anxiety, flashbacks, and insomnia (Wells et al., 1991), although no controlled studies of this agent have been published in childhood populations. 

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-... 

HTia partial agonists), very different from those of the selective serotonin reuptake inhibitors (SSRIs) and the other antidepressants used to treat anxiety disorders. Buspirone does not cause sedation and has minimal or no potential for abuse or dependence, in contrast to most benzodiazepines. 

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. 

Kuipers W, van Wijngaarden I, Ijzerman AP. A model of the serotonin 5-HTia receptor agonist and antagonist binding sites. Drug Design Discov 1994 1 1 231-249. 

Heinrich, T, Bottcher, H., Gericke, R., Bartoszyk, G.D., Anzali, S., Seyfried, C.A., Greiner, H.E., and van Amsterdam, C. (2004) Synthesis and structure-activity relationship in a class of indolebutylpiperazines as dual 5-HTia receptor agonists and serotonin reuptake... 

Sprouse, J. S. Aghajanian, G. K. (1988). Responses of hippocampal pyramidal cells to putative serotonin 5-HTia and 5-HTib agonists a comparative study with dorsal raphe neurons. Neuropsychopharmacology 27, 707 15. 

Koella has reviewed the evidence implicating the involvement of serotonin in the sleep-wake cycle but the involvement of specific serotonin receptor subtypes in sleep mechanisms is unclear. Experimental evidence suggests that 5-HTia agonists delay the onset of REM sleep while 5-HT2 antagonists suppress REM and have variable effects on non-REM sleep. 

Although buspirone has been shown to interact with a number of neurotransmitter systems in the brain, it appears that its clinically relevant effects are mediated through interactions at the serotonin (5-hydroxytrypta-mine, 5-HT) 5-HTia receptor, where it acts as a partial agonist. 

Trazodone (Apothecon) is also classified as an antidepressant agent. It is a selective serotonin reuptake inhibitor (SSRI), partial agonist at postsynaptic 5-HTia receptors, and exhibits a-adrenoceptor blocking actions. 

Buspirone is an anxiolytic with dopaminergic, noradrenergic and antiserotonergic properties, Anxiolytic properties are attributed to effects on serotonin transmission (probably inhibiting transmission via 5-HTLA autoregulation). It may have postsynaptic 5-HTIA agonist activity and thus facilitate serotonin neurotransmission. 

Lesopitron is a non-benzodiazepine anxioljdic drug. Its structure is similar to that of buspirone, and it is an agonist at central serotonin (5-HTia) receptors. 

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