title: BF2.649 [1-{3-[3-(4-Chlorophenyl)propoxy]propyl}piperidine, hydrochloride], a nonimidazole inverse agonist/antagonist at the human histamine H3 receptor: Preclinical pharmacology.
abstract: Histamine H3 receptor inverse agonists are known to enhance the activity of histaminergic neurons in brain and thereby promote vigilance and cognition. 1-{3-[3-(4-Chlorophenyl)propoxy]propyl}piperidine, hydrochloride (BF2.649) is a novel, potent, and selective nonimidazole inverse agonist at the recombinant human H3 receptor. On the stimulation of guanosine 5'-O-(3-[35S]thio)triphosphate binding to this receptor, BF2.649 behaved as a competitive antagonist with a Ki value of 0.16 nM and as an inverse agonist with an EC50 value of 1.5 nM and an intrinsic activity approximately 50% higher than that of ciproxifan. Its in vitro potency was approximately 6 times lower at the rodent receptor. In mice, the oral bioavailability coefficient, i.e., the ratio of plasma areas under the curve after oral and i.v. administrations, respectively, was 84%. BF2.649 dose dependently enhanced tele-methylhistamine levels in mouse brain, an index of histaminergic neuron activity, with an ED50 value of 1.6 mg/kg p.o., a response that persisted after repeated administrations for 17 days. In rats, the drug enhanced dopamine and acetylcholine levels in microdialysates of the prefrontal cortex. In cats, it markedly enhanced wakefulness at the expense of sleep states and also enhanced fast cortical rhythms of the electroencephalogram, known to be associated with improved vigilance. On the two-trial object recognition test in mice, a promnesiant effect was shown regarding either scopolamine-induced or natural forgetting. These preclinical data suggest that BF2.649 is a valuable drug candidate to be developed in wakefulness or memory deficits and other cognitive disorders.
authors.affiliation: Bioprojet-Biotech, Saint Grégoire, France.
authors.forename: X
authors.initials: X
authors.lastname: Ligneau
authors.forename: D
authors.initials: D
authors.lastname: Perrin
authors.forename: L
authors.initials: L
authors.lastname: Landais
authors.forename: J-C
authors.initials: JC
authors.lastname: Camelin
authors.forename: T P G
authors.initials: TP
authors.lastname: Calmels
authors.forename: I
authors.initials: I
authors.lastname: Berrebi-Bertrand
authors.forename: J-M
authors.initials: JM
authors.lastname: Lecomte
authors.forename: R
authors.initials: R
authors.lastname: Parmentier
authors.forename: C
authors.initials: C
authors.lastname: Anaclet
authors.forename: J-S
authors.initials: JS
authors.lastname: Lin
authors.forename: V
authors.initials: V
authors.lastname: Bertaina-Anglade
authors.forename: C Drieu
authors.initials: CD
authors.lastname: la Rochelle
authors.forename: F
authors.initials: F
authors.lastname: d'Aniello
authors.forename: A
authors.initials: A
authors.lastname: Rouleau
authors.forename: F
authors.initials: F
authors.lastname: Gbahou
authors.forename: J-M
authors.initials: JM
authors.lastname: Arrang
authors.forename: C R
authors.initials: CR
authors.lastname: Ganellin
authors.forename: H
authors.initials: H
authors.lastname: Stark
authors.forename: W
authors.initials: W
authors.lastname: Schunack
authors.forename: J-C
authors.initials: JC
authors.lastname: Schwartz
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D002415:Cats; D004298:Dopamine / Q000378:metabolism; D004569:Electroencephalography / Q000187:drug effects; D006168:Guinea Pigs; D017442:Histamine Agonists / Q000494:pharmacology*; D006633:Histamine Antagonists / Q000494:pharmacology*; D006636:Histamine Release / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000378:metabolism; D008297:Male; D008761:Methylhistamines / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D010880:Piperidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D018100:Receptors, Histamine H3 / Q000187:drug effects* / Q000502:physiology; D012601:Scopolamine / Q000494:pharmacology
chemical_list: D017442:Histamine Agonists; D006633:Histamine Antagonists; D007093:Imidazoles; D008761:Methylhistamines; D010880:Piperidines; D018100:Receptors, Histamine H3; C090115:iodoproxyfan; C516975:pitolisant; D012601:Scopolamine; C020404:tele-methylhistamine; D000109:Acetylcholine; D004298:Dopamine