Novel atypical antipsychotic agents: rational design, an efficient palladium-catalyzed route, and pharmacological studies.
Using rational drug design to develop atypical antipsychotic drug candidates, we generated novel and metabolically stable pyrrolobenzazepines with an optimized pK(i) 5-HT(2A)/D(2) ratio. 5a, obtained by a new palladium-catalyzed three-step synthesis, was selected for further pharmacological and biochemical investigations and showed atypical antipsychotic properties in vivo. 5a was active on conditioned avoidance response at 0.56 mg/kg, it had low cataleptic potential and proved to be better than ST1899, clozapine, and olanzapine, representing a new clinical candidate.
Campiani
Giuseppe
G
Dipartimento Farmaco Chimico Tecnologico, Via Aldo Moro, and European Research Centre for Drug Discovery and Development, Università di Siena, 53100 Siena, Italy. campiani@unisi.it
Butini
Stefania
S
Fattorusso
Caterina
C
Trotta
Francesco
F
Gemma
Sandra
S
Catalanotti
Bruno
B
Nacci
Vito
V
Fiorini
Isabella
I
Cagnotto
Alfredo
A
Mereghetti
Ilario
I
Mennini
Tiziana
T
Minetti
Patrizia
P
Di Cesare
M Assunta
MA
Stasi
M Antonietta
MA
Di Serio
Stefano
S
Ghirardi
Orlando
O
Tinti
Ornella
O
Carminati
Paolo
P
D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects; D001552:Benzazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002375:Catalepsy / Q000139:chemically induced; D002384:Catalysis; D002460:Cell Line; D018360:Crystallography, X-Ray; D065127:Dopamine D2 Receptor Antagonists; D015195:Drug Design; D066298:In Vitro Techniques; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D010165:Palladium; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A / Q000737:chemistry; D017448:Receptors, Dopamine D2 / Q000737:chemistry; D058830:Serotonin 5-HT2 Receptor Antagonists; D013329:Structure-Activity Relationship
D014150:Antipsychotic Agents; D001552:Benzazepines; D065127:Dopamine D2 Receptor Antagonists; D011758:Pyrroles; D044402:Receptor, Serotonin, 5-HT2A; D017448:Receptors, Dopamine D2; D058830:Serotonin 5-HT2 Receptor Antagonists; D010165:Palladium