Design, synthesis, and pharmacological evaluation of multitarget-directed ligands with both serotonergic subtype 4 receptor (5-HT4R) partial agonist and 5-HT6R antagonist activities, as potential treatment of Alzheimer's disease.
5-HT4 receptor (5-HT4R) activation and blockade of the 5-HT6 receptor (5-HT6R) are known to enhance the release of numerous neurotransmitters whose depletion is implicated in Alzheimer's disease (AD). Furthermore, 5-HT4R agonists seem to favor production of the neurotrophic soluble amyloid protein precursor alpha (sAPPα). Consequently, combining 5-HT4R agonist/5-HT6R antagonist activities in a single chemical compound would constitute a novel approach able to display both a symptomatic and disease-modifying effect in AD. Seventeen novel derivatives of RS67333 (1) were synthesized and evaluated as potential dual-target compounds. Among them, four agents showed nanomolar and submicromolar affinities toward 5-HT4R and 5-HT6R, respectively; one of them, 7m, was selected on the basis of its in vitro affinity (Ki5-HT4R = 5.3 nM, Ki5-HT6R = 219 nM) for further in vivo experiments, where 7m showed an antiamnesic effect in the mouse at 1 mg/kg ip.
Normandie Université, UNICAEN, CERMN (Centre d'Etudes et de Recherche sur le Médicament de Normandie), F-14032, Caen, France.
Samir
S
Yahiaoui
Normandie Université, UNICAEN, GMPc (Groupe Mémoire et Plasticité comportementale), F-14032, Caen, France.
Katia
K
Hamidouche
Normandie Université, UNICAEN, CERMN (Centre d'Etudes et de Recherche sur le Médicament de Normandie), F-14032, Caen, France.
Céline
C
Ballandonne
Normandie Université, UNICAEN, CERMN (Centre d'Etudes et de Recherche sur le Médicament de Normandie), F-14032, Caen, France.
Audrey
A
Davis
Normandie Université, UNICAEN, CERMN (Centre d'Etudes et de Recherche sur le Médicament de Normandie), F-14032, Caen, France.
Jana Sopkova
JS
de Oliveira Santos
Normandie Université, UNICAEN, GMPc (Groupe Mémoire et Plasticité comportementale), F-14032, Caen, France.
Thomas
T
Freret
Normandie Université, UNICAEN, GMPc (Groupe Mémoire et Plasticité comportementale), F-14032, Caen, France.
Michel
M
Boulouard
Normandie Université, UNICAEN, CERMN (Centre d'Etudes et de Recherche sur le Médicament de Normandie), F-14032, Caen, France. Electronic address: christophe.rochais@unicaen.fr.
Christophe
C
Rochais
Normandie Université, UNICAEN, CERMN (Centre d'Etudes et de Recherche sur le Médicament de Normandie), F-14032, Caen, France. Electronic address: patrick.dallemagne@unicaen.fr.
Patrick
P
Dallemagne
D000544:Alzheimer Disease / Q000188:drug therapy*; D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D006168:Guinea Pigs; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D058990:Molecular Targeted Therapy; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011985:Receptors, Serotonin / Q000378:metabolism*; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism*; D058828:Serotonin 5-HT4 Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
D000814:Aniline Compounds; D008024:Ligands; D010880:Piperidines; D011985:Receptors, Serotonin; D058828:Serotonin 5-HT4 Receptor Agonists; D012702:Serotonin Antagonists; C097216:serotonin 6 receptor; D044422:Receptors, Serotonin, 5-HT4; C107826:RS 67333
5-HT(4) receptors agonists; 5-HT(6) receptors antagonists; Alzheimer’s disease; MTDL