Therapeutic Potential of 5-HT 6 Receptor Agonists

Delphine Karila (1) , Thomas Freret (2) , Valentine Bouet (3) , Michel Boulouard (2) , Patrick Dallemagne (4) , Christophe Rochais (4)

1 ICSN - Institut de Chimie des Substances Naturelles
2 GMPc - Groupe Mémoire et Plasticité comportementale
3 UB - Université de Bordeaux
4 CERMN - Centre d'Etudes et de Recherche sur le Médicament de Normandie

Given its predominant expression in the central nervous system (CNS), 5-hydroxytryptamine (5-HT: serotonin) subtype 6 receptor (5-HT6R) has been considered as a valuable target for the development of CNS drugs with limited side effects. After 2 decades of intense research, numerous selective ligands have been developed to target this receptor; this holds potential interest for the treatment of neuropathological disorders. In fact, some agents (mainly antagonists) are currently undergoing clinical trial. More recently, a series of potent and selective agonists have been developed, and preclinical studies have been conducted that suggest the therapeutic interest of 5-HT6R agonists. This review details the medicinal chemistry of these agonists, highlights their activities, and discusses their potential for treating cognitive issues associated with Alzheimer's disease (AD), depression, or obesity. Surprisingly, some studies have shown that both 5-HT6R agonists and antagonists exert similar procognitive activities. This article summarizes the hypotheses that could explain this paradox

Mots clés: Antagonists; Agonists; Ligands; Rodent models; Receptors

Domaines: Chimie thérapeutique

Delphine Karila, Thomas Freret, Valentine Bouet, Michel Boulouard, Patrick Dallemagne, et al.. Therapeutic Potential of 5-HT 6 Receptor Agonists. Journal of Medicinal Chemistry, 2015, 58 (20), pp.7901-7912. ⟨10.1021/acs.jmedchem.5b00179⟩. ⟨hal-02043781⟩