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 H₁Receptor Affinity Than Olanzapine

Abstract

FMPD [6-fluoro-10-[3-(2-methoxyethyl)-4-methyl-piperazin-1-yl]-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 ϭ 6.3 nM), 5-HT 2A (K i ϭ 7.3 nM), and 5-HT 6 (K i ϭ 8.0 nM) human recombinant receptors and lower affinity for histamine H 1 (K i ϭ 30 nM) and 5-HT 2C (K i ϭ 102 nM) human recombinant receptors than olanzapine. Oral administration of FMPD increased rat nucleus accumbens 3,4-dihyroxyphenylacetic acid concentrations (ED 200 ϭ 6 mg/kg), blocked 5-HT 2A agonist-induced increases in rat serum corticosterone levels (ED 50 ϭ 1.8 mg/kg), and inhibited the ex vivo binding of [ 125 I]SB-258585 [4-iodo-N-[4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-benzenesulfonamide] to striatal 5-HT 6 receptors (ED 50 ϭ 10 mg/kg) but failed to inhibit ex vivo binding of [ 3 H]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-HT 2A , and 5-HT 6 receptors and a weak antagonist of H 1 and 5-HT 2C receptors. FMPD has the potential to have efficacy in treating schizophrenia and bipolar mania with a low risk of treatmentemergent extrapyramidal symptoms, prolactin elevation, and weight gain. Clinical trials are needed to test these hypotheses.Olanzapine is effective in treating schizophrenia and bipolar mania (Beasley et al., 1996;Tohen et al., 2000). It is classified as an atypical antipsychotic in that it has therapeutic effects on the positive, negative, and cognitive symptoms of schizophrenia while having a low propensity to produce extrapyramidal symptoms (EPS) and prolactin elevation. However, many patients have observed weight gain associated with the treatment of olanzapine and other atypical antipsychotics (Wirshing, 2001).It has been hypothesized that blockade of the histamine H 1 receptor plays a critical role in antipsychotic treatmentemergent weight gain. Histamine has long been associated with the control of food intake. Histamine activates postsynaptic H 1 receptors in the ventromedial and para-ventricular nucleus of the hypothalamus to suppress feeding (Sakata et al., 1988;Ookuma et al., 1989), and H 1 knock-out mice develop diet-induced and age-related obesity (Masaki et al., 2001). In addition, a significant correlation between affinity for the human H 1 receptor and weight gain has been reported for antipsychotics (Kroeze et al., 2003). Thus, an a...

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