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 H 3 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 H 3 receptor. On the stimulation of guanosine 5Ј-O-(3-[35 S]thio)triphosphate binding to this receptor, BF2.649 behaved as a competitive antagonist with a K i value of 0.16 nM and as an inverse agonist with an EC 50 value of 1.5 nM and an intrinsic activity ϳ50% higher than that of ciproxifan. Its in vitro potency was ϳ6 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 ED 50 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.The cerebral histaminergic neurons seem to play a critical role in the maintenance of wakefulness and higher cerebral functions, e.g., attention or learning (for review, see Schwartz et al., 1991;Haas and Panula, 2003). Hence, druginduced activation of histaminergic neurotransmission in the central nervous system represents a promising therapeutic target in a large variety of neuropsychiatric disorders in which these functions are compromised and for which available therapeutic opportunities are limited in this respect .Stimulation of postsynaptic H 1 and/or H 2 receptors by agonists is, however, not acceptable due to unavoidable and detrimental actions of these drugs at peripheral, i.e., mainly cardiovascular and gastric targets. In contrast, presynaptic H 3 receptors are almost exclusively expressed in the central nervous system, and their blockade by drugs such as thioperamide markedly enhances the activity of histaminergic neurons, as shown namely by the increases in histamine (HA) release and turnover in rodent brain (Arrang et al., Article, publication date, and citation information can be found at

Brain histamine and schizophrenia: Potential therapeutic applications of H3-receptor inverse agonists studied with BF2.649

“…Second, the cognitive deficit is certainly one of the symptoms which are the most resistant to current medications. In the case of BF2.649, a promnesiant effect accompanied with a shift of the EEG patterns towards high frequency waves, characteristic of cortical activation and a pro-attention effect, was previously demonstrated in cats [15] and is also observed here to accompany the wakening effect of the drug in mice.…”

“…In mice, oral administration of BF2.649 caused a dose-dependent reduction of neocortical slow activity (at δ range 0.8-2.5 Hz) and spindles (8)(9)(10)(11)(12)(13)(14)(15) and an increase in power spectral density of neocortical fast rhythms (β and γ bands, mainly 30-60 Hz) resulting in a marked enhancement of cortical activation, i.e. low voltage and fast electrical activity with dominant waves in the β and γ bands (Fig.…”

“…The mechanism underlying this functional antagonism of behavioural responses elicited by direct or indirect dopamine agonists is far from clear. A direct antagonism at dopamine receptors cannot be invoked in view of the high degree of pharmacological specificity of BF2.649 [15]; also this drug effect consisted in a partial decrease of the response to the dopamine agonists, which was, even, not significant in the case of the apomorphine-induced climbing behaviour.…”

An inverse agonist of the histamine H3 receptor improves wakefulness in narcolepsy: Studies in orexin−/− mice and patients

“…Both tiprolisant and modafinil enhanced wakefulness during the lights-off (active) period in orexin-/-mice, as is observed in WT rodents (Scammell et al,2000;Parmentier et al,2007;Ligneau et al,2007b) and cats (Lin et al,1992;Ligneau et al,1998Ligneau et al, ,2007a.…”

“…We examined this hypothesis, first using a reliable animal model of narcolepsy, the orexin-/-mouse, which displays DREMs, a characteristic symptom of the disease (Chemelli et al, 1999;Mignot, 2005;Fujiki, et al, 2006), then in narcoleptic patients, by testing the effects of tiprolisant (BF2.649), a potent and selective inverse agonist of the H3 receptors (Ligneau et al, 2007a and2007b) in both proof-of-concept studies. This class of agents is known to promote wakefulness by inhibiting the constitutively active H3-autoreceptor, thereby enhancing histaminergic neuron activity and histamine (HA) release (Schwartz et al, 1991;Lin, 2000;Morisset et al, 2000;Vanni-Mercier et al, 2003;Parmentier et al, 2002Parmentier et al, , 2007.…”