PRECLINICAL CHARACTERIZATION OF THE POTENTIAL OF THE PUTATIVE ATYPICAL ANTIPSYCHOTIC MDL-100,907 AS A POTENT 5-HT2A ANTAGONIST WITH A FAVORABLE CNS SAFETY PROFILE

In preclinical studies, -1-[2-(4-fluorophenyl)ethyl]-4-piperidinemetha nol] (MDL 100,907), a putative atypical antipsychotic, was characteriz ed in vitro as a potent and selective ligand for the serotonin(2A) (5- HT2A) receptor and was evaluated in vitro and in vivo as a potent 5-HT 2A receptor antagonist. Furthermore, MDL 100,907's potential CNS safet y profile and selectivity as a potential antipsychotic agent were eval uated and compared with benchmark compounds. MDL 100,907 demonstrated low nanomolar or subnanomolar binding in vitro at the 5-HT2A receptor and showed a >100-fold separation from all other receptors measured. M DL 100,907 had subnanomolar potency as a 5-HT2A antagonist in vitro in reversing 5-HT-stimulated inositol phosphate accumulation in NIH 3T3 cells transfected with the rat 5-HT2A receptor. In vivo, MDL 100,907 p otently inhibited 5-methoxy-N,N-dimethyltryptamine-induced head twitch es in mice or 5-hydroxytryptophan-induced head twitches in rats. In vi vo functional tests in mice revealed a >500-fold separation between do ses that produced 5-HT2A antagonism and doses that produced alpha(1)-a drenergic or striatal D-2 antagonism. Using inhibition of D-amphetamin e-stimulated locomotion in mice as a measure of potential antipsychoti c efficacy, MDL 100,907 showed a superior CNS safety index relative to the reference compounds, haloperidol, clozapine, risperidone, ritanse rin, and amperozide, in each of five tests for side effect potential, including measures of ataxia, general depressant effects, alpha,adrene rgic antagonism, striatal D-2 receptor antagonism, and muscle relaxati on. MDL 100,907 did not antagonize apomorphine-induced stereotypies in rats, suggesting that it potentially lacks extrapyramidal side effect liability. MDL 100,907 showed selectivity as a potential antipsychoti c in that it lacked consistent activity in selected rodent models of a nticonvulsant, antidepressant, analgesic, or anxiolytic activity. In s ummary, these preclinical data indicate that MDL 100,907 is a potent a nd selective ligand at the 5-HT2A receptor. MDL 100,907's potent 5-HT2 A antagonist activity might account for its activity in preclinical mo dels of antipsychotic potential. Ongoing clinical evaluation with MDL 100,907 will lest the hypothesis that 5-HT2A receptor antagonism is su fficient for antipsychotic activity in humans.