Neuropharmacology 2006 May 10; (Read article online)

Brea J, Castro M, Loza MI, Masaguer CF, Raviña E, Dezi C, Pastor M, Sanz F, Cabrero-Castel A, Galán-Rodríguez B, Fernández-Espejo E, Maldonado R, Robledo P

The aim of the present work was to characterize a lead compound displaying relevant multi-target interactions, and with an in vivo behavioral profile predictive of atypical antipsychotic activity. Synthesis, molecular modeling and in vitro and in vivo pharmacological studies were carried out for 2-[4-(6-fluorobenzisoxazol-3-yl)piperidinyl]methyl-1,2,3,4-tetrahydro-carbazol-4-one (QF2004B), a conformationally constrained butyrophenone analogue. This compound showed a multi-receptor profile with affinities similar to those of clozapine for serotonin (5-HT(2A), 5-HT(1A), and 5-HT(2C)), dopamine (D(1), D(2), D(3) and D(4)), alpha-adrenergic (alpha(1), alpha(2)), muscarinic (M(1), M(2)) and histamine H(1) receptors. In addition, QF2004B mirrored the antipsychotic activity and atypical profile of clozapine in a broad battery of in vivo tests including locomotor activity (ED(50)=1.19mg/kg), apomorphine-induced stereotypies (ED(50)=0.75mg/kg), catalepsy (ED(50)=2.13mg/kg), apomorphine- and DOI (2,5-dimethoxy-4-iodoamphetamine)-induced prepulse inhibition (PPI) tests. These results point to QF2004B as a new lead compound with a relevant multi-receptor interaction profile for the discovery and development of new antipsychotics.