An initial three-component pharmacophore for specific serotonin-3 receptor ligands.
With computer modeling, an initial three-component pharmacophore for specific 5-HT3 receptor ligands ICS-205-930 (1), ondansetron (2), zacopride (3), and 3-[2-(guanidinylmethyl)-4-thiazolyl]indol (4) has been identified. Two parts represent electrostatic interactions, one as a hydrogen-bond-donating interaction and the other as a hydrogen-bond-accepting interaction. The third part is represented by a plane in which the lipophilic aromatic groups align. The generation of the pharmacophore relies on the interactions of these ligands with probe atoms representative of a possible hydrogen-bond donor or hydrogen-bond acceptor within the receptor. A carboxylate oxygen was used as a hydrogen-bond-accepting probe and a serine-like hydroxyl was utilized as a hydrogen-bond-donating probe.
Rizzi
J P
JP
Central Research Division, Pfizer Inc., Groton, Connecticut 06340.
Nagel
A A
AA
Rosen
T
T
McLean
S
S
Seeger
T
T
D000818:Animals; D001549:Benzamides / Q000737:chemistry; D001643:Bridged Bicyclo Compounds / Q000737:chemistry; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003196:Computer Graphics; D003198:Computer Simulation; D007093:Imidazoles / Q000737:chemistry; D066298:In Vitro Techniques; D007211:Indoles / Q000737:chemistry; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D017294:Ondansetron; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects*; D012702:Serotonin Antagonists; D013329:Structure-Activity Relationship; D013844:Thiazoles; D000077526:Tropisetron
D001549:Benzamides; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007093:Imidazoles; D007211:Indoles; D008024:Ligands; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013844:Thiazoles; D017294:Ondansetron; D000077526:Tropisetron; C055971:zacopride