5-HT3 receptor agonists and

The indole analogue GR 65630 (34) has been used as a radioactive ligand in studies of binding of various 5-HT3 receptor agonists and antagonists [28],... 

Fig. 3. Examples of 5-HT3 agonist and antagonist pharmacophores. Serotonin (A) and granisetron (B) are shown as examples of 5-HT3 receptor agonists and antagonists. Both molecules are shown as stick models. Electrostatic potential is displayed in wire frame. Attention has been drawn to the important features of each pharmacophore.

A second assay which has been used extensively in the characterization of 5-HT3 receptors is the rabbit isolated heart. Both the sympathetic and parasympathetic inputs to the rabbit heart can be influenced by stimulation of 5-HT3 receptors this preparation is usually performed in the presence of atropine to block parasympathetic effects [12]. Under these conditions, 5-HT and other 5-HT3 receptor agonists exert positive effects on rate and contractile force. Selective 5-HT3 receptor antagonists such as MDL 72222 [6], ICS 205-930 [3] and ondansetron [7] block the agonist effects in a concentration-related manner. 

At about the same time that 5-HTQ was identified, it was reported that phenylbiguanide (27) represents a novel type of 5-HT3 agonist (47). Arylpiper-azines (28) were also found to bind at 5-HT3 receptors (48), and some were... 

Metoclopramide is a first-generation benzamide. The drug acts presynaptically, mainly as a 5-hydroxytryptamine (5-HT serotonin) 5-HT4 receptor agonist and 5-HT3 receptor antagonist but it is also an antagonist at dopamine 1 (Dj) and 2 (D2) receptors (MacDonald 1991). The net effect of the interactions with these receptors is to facilitate acetylcholine release from enteric neurons and promote smooth muscle contrachon. Metoclopramide... 

Campiani G, Cappelli A, Nacci V, et al. Novel and highly potent 5-HT3 receptor agonists based on a pyrroloquinozaline structure. J Med Chem 1997 40 3670-3678. 

Some derivatives of adamantane with antagonist or agonist effects have also been synthesized. For instance, monocationic and dicationic adamantane derivatives block the a-amino-3-hydroxy-5-methylisoxazole -propionic acid (AMPA) receptors, A-methyl-o-aspartate (NMDA) receptors [134—136] and 5-hydroxytryptamine (5-HT3) receptors [137]. 

The 5-HT3 receptor is found appropriately in mesocortical areas and while behavioural studies with their antagonists in rodents showed potential antipsychotic activity, they have proved ineffective in patients. 5-HTia agonists may be more useful. They have been found to increase the extracellular concentration of DA in the frontal cortex of rats but diminish apomorphine-induced stereotypy (striatal effect). So they could be of some benefit, especially against negative symptoms, without causing EPSPs (see Chapter 9). 

Not much is known about the role of the 5-HT3 receptor in the regulation of sleep and waking. A limited number of selective agonists for the... 

Mirtazapine (Remeron) is a newer antidepressant that also blocks 5-HT reuptake, but additionally has antagonistic effects at adrenergic o2, 5-HT2, and 5-HT3 receptors (Stahl 1998). Mirtazapine appears to have indirect agonistic effects on 5-HTlA receptors, which may contribute to its antidepressant effect (Berendsen and Broekkamp 1997). Nefazodone, as well, has SSRI and 5-HT2 antagonist effects. The 5-HT2 antagonist effects of these antidepressants is believed to be responsible for their lower incidence of sexual side effects (Nutt 1997). 

HT3 receptor agonists have been shown to enhance the release of endogenous dopamine from striatal slices [14] and to reduce acetylcholine release from sections of rat entorhinal cortex [15]. Furthermore, there are several electrophysiological techniques using a variety of neurones, including those in the gut [25] and primary cultures of brain tissue [26] which respond to 5-HT3 agonist stimulation. 

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