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NEUROPHARMACOLOGY

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

Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, Indiana (K.R., M.J.B., F.P.B., D.O.C., I.R.C., J.F.F., S.K.H.L., L.K.N., J.M.S., S.J.S., T.R.W., D.L.N.) and Surrey, United Kingdom (F.M.M., N.A.M., D.E.T.)

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 D₂ (K_i = 6.3 nM), 5-HT_2A (K_i = 7.3 nM), and 5-HT₆ (K_i = 8.0 nM) human recombinant receptors and lower affinity for histamine H₁ (K_i = 30 nM) and 5-HT_2C (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-HT_2A agonist-induced increases in rat serum corticosterone levels (ED₅₀ = 1.8 mg/kg), and inhibited the ex vivo binding of [¹²⁵I]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 [³H]pyrilamine to hypothalamic histamine H₁ 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 D₂, 5-HT_2A, and 5-HT₆ receptors and a weak antagonist of H₁ and 5-HT_2C 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.

Address correspondence to: Dr. Kurt Rasmussen, Lilly Research Laboratories, Eli Lilly and Co., Lilly Corporate Center, Indianapolis, IN 46285. E-mail: rasmussen_kurt{at}lilly.com

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