Medicinal Chemistry of 5-HT5A Receptor Ligands: A Receptor Subtype with Unique Therapeutical Potential

Abstract

Although the 5-HT(5) receptor subfamily was discovered more than 15 years ago, it is unambiguously the least known 5-HT receptor subtype. The G(i)/G(0)-mediated signal transduction and its intensive presence in raphe and other brainstem and pons nuclei suggest mechanisms similar to those of 5-HT(1) receptors, the ligands of which are already applied in the treatment of e.g. anxiety and migraine. In addition, a unique coupling and inhibition of adenosine diphosphate-ribosyl cyclase have also been described. High concentrations of 5-HT(5) receptor in other key regions including, e.g. locus coeruleus, nucleus of the solitary tract, arcuate and suprachiasmatic nuclei of the hypothalamus indicate a wide range of physiological effects, thus its ligands are potential drug candidates in various areas, e.g. anxiety, sleep, incontinence, food intake, learning and memory, pain or chemoreception pathways. These findings have motivated several institutes and pharmaceutical companies to participate in the research of this field. Despite extensive research, no selective agonist and only two selective antagonists have been identified until now. Beyond these compounds, the present review provides a complete overview on all other published 5-HT(5A) receptor ligands as well as on the structure, function, distribution, genetics and possible therapeutic applications of this receptor.

5-HT2A receptor activation is necessary for CO2-induced arousal

“…Given that other 5-HT receptors are also present in the thalamus and cortex and have been implicated in sleep-wake regulation (Monti 2011;Volk et al 2010), we tested whether blockade of any of these receptor subtypes could impair CO 2 -induced arousal. The 5-HT 3 receptor antagonist, ondansetron; the 5-HT 4 receptor antagonist, GR-125487; the 5-HT 5 receptor antagonist, SB-699551; the 5-HT 6 receptor antagonist, Ro4368554; and the 5-HT 7 receptor antagonist SB-269970 had no effect on CO 2 -induced arousal (Fig.…”

Serotonin and molecular neuroimaging in humans using PET

“…Although highly 5-ht 5A selective antagonists were tested in guinea pig (SB699551-A, Thomas et al 2006) and rodent (A843277, Volk et al 2010), no selective PET ligand has yet been successfully synthesized, obscuring the receptor's function in vivo.…”

P2Y2 receptor signaling in neutrophils is regulated from inside by a novel cytoskeleton-dependent mechanism

“…These agonist-induced changes may thus lead to biased signaling, defined as ligand-dependent selectivity, i.e., the activation of particular signal transduction pathways and the pathway chosen is determined by the precise conformational change in the receptor induced by the bound agonist. A prominent example is the 5-hydoxy-tryptamine (serotonin) receptor (5-HTR); when activated by serotonin and other agonists, different signaling routes are initiated [6].…”