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 D2 (Ki= 6.3 nM), 5-HT(2A) (Ki= 7.3 nM), and 5-HT6 (Ki= 8.0 nM) human recombinant receptors and lower affinity for histamine H1 (Ki= 30 nM) and 5-HT2C (Ki= 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 [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-HT2A, and 5-HT6 receptors and a weak antagonist of H1 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.
Subject(s)
Antipsychotic Agents/pharmacology , Piperazines/pharmacology , Receptors, Histamine H1/metabolism , 3,4-Dihydroxyphenylacetic Acid/analysis , 3,4-Dihydroxyphenylacetic Acid/metabolism , Animals , Antipsychotic Agents/metabolism , Benzodiazepines/chemistry , Benzodiazepines/metabolism , Benzodiazepines/pharmacology , Benzodiazepines/therapeutic use , Body Weight/drug effects , Catalepsy/chemically induced , Cocaine/pharmacology , Corticosterone/blood , Drug Evaluation, Preclinical , Electrochemistry , Electrophysiology , Fasting , Female , Immunohistochemistry , Male , Molecular Structure , Motor Activity/drug effects , Nucleus Accumbens/metabolism , Olanzapine , Piperazines/chemistry , Piperazines/metabolism , Prolactin/blood , Quipazine/pharmacology , Radioligand Assay , Rats , Rats, Inbred F344 , Rats, Inbred Strains , Rats, Sprague-Dawley , Serotonin Receptor Agonists/pharmacology , Thiophenes/chemistry , Thiophenes/pharmacology , Thiophenes/therapeutic use , Time FactorsABSTRACT
A series of substituted naphthyl containing chiral [2.2.1] bicycloheptanes were prepared utilizing asymmetric Diels-Alder chemistry. This paper describes structure-activity relationships in this series. The N-methyl 2-naphthyl analogue (16d) and its des-methyl analogue (17d) are active triple re-uptake inhibitors both in vivo and in vitro.
