Preclinical pharmacology of FMPD [6-fluoro-10-[3-(2-methoxyethyl)-4-methyl-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene]: a potential novel antipsychotic with lower histamine H1 receptor affinity than olanzapine.

FMPD [6-fluoro-10-[3-(2-methoxyethyl)-4-methyl-piperazin-1yl]- 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene] is a potential novel antipsychotic with high affinity for dopamine D-2 ( K-i = 6.3 nM), 5-HT2A (K-i = 7.3 nM), and 5-HT6 (K-i = 8.0 nM) human recombinant receptors and lower affinity for histamine H-1 (K-i= 30 nM) and 5-HT2C ( K-i = 102 nM) human recombinant receptors than olanzapine. Oral administration of FMPD increased rat nucleus accumbens 3,4-dihyroxyphenylacetic acid concentrations (ED200 = 6 mg/ kg), blocked 5-HT2A agonist-induced increases in rat serum corticosterone levels (ED50 = 1.8 mg/kg), and inhibited the ex vivo binding of [I-125]SB-258585 [4-iodo-N-[ 4-methoxy-3-(4-methyl-piperazin-1-yl)- phenyl]- benzenesulfonamide] to striatal 5-HT6 receptors (ED50 = 10 mg/kg) but failed to inhibit ex vivo binding of [H-3] pyrilamine to hypothalamic histamine H-1 receptors at doses of up to 30 mg/kg. In electrophysiology studies, acute administration of FMPD selectively elevated the number of spontaneously active A10 ( versus A9) dopamine neurons and chronic administration selectively decreased the number of spontaneously active A10 ( versus A9) dopamine neurons. FMPD did not produce catalepsy at doses lower than 25 mg/kg p.o. In Fos-induction studies, FMPD had an atypical antipsychotic profile in the striatum and nucleus accumbens and increased Fos expression in orexin-containing neurons of the hypothalamus. FMPD produced only a transient elevation of prolactin levels. These data indicate that FMPD is an orally available potent antagonist of dopamine D-2, 5-HT2A, and 5-HT6 receptors and a weak antagonist of H-1 and 5-HT2C receptors. FMPD has the potential to have efficacy in treating schizophrenia and bipolar mania with a low risk of treatment-emergent extrapyramidal symptoms, prolactin elevation, and weight gain. Clinical trials are needed to test these hypotheses.