Pharmacological Properties of ABT-239 [4-(2-{2-[(2R)-2-Methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile]: I. Potent and Selective Histamine H₃ Receptor Antagonist with Drug-Like Properties

Abstract

Histamine H 3 receptor antagonists are being developed to treat a variety of neurological and cognitive disorders that may be ameliorated by enhancement of central neurotransmitter release. Here, we present the in vitro pharmacological and in vivo pharmacokinetic profiles for the nonimidazole, benzofuran ligand ABT-239 [4-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile] and compare it with several previously described imidazole and nonimidazole H 3 receptor antagonists. ABT-239 binds to recombinant human and rat H 3 receptors with high affinity, with pK i values of 9.4 and 8.9, respectively, and is over 1000-fold selective versus human H 1 , H 2 , and H 4 histamine receptors. ABT-239 is a potent H 3 receptor antagonist at recombinant human and rat receptors, reversing agonist-induced changes in cAMP formation (pK b ϭ 7.9 and 7.6, respectively), guanosine 5Ј-O-(3-[ ]GTP␥S binding at both rat and human H 3 receptors with respective pEC 50 values of 8.9 and 8.2. ABT-239 demonstrates good pharmacokinetic characteristics in rat, dog, and monkey with t 1/2 values ranging from 4 to 29 h, corresponding with clearance values and metabolic turnover in liver microsomes from these species, and good oral bioavailability ranging from 52 to 89%. Thus, ABT-239 is a selective, nonimidazole H 3 receptor antagonist/inverse agonist with similar high potency in both human and rat and favorable drug-like properties.Histamine H 3 receptors are G protein-coupled receptors that function as central autoreceptors to modulate the release of histamine (Arrang et al., 1983). H 3 receptors also function as heteroreceptors, regulating the release of other important neurotransmitters such as acetylcholine, dopamine, norepinephrine, and serotonin, among others (Blandina et al., 1998) that seem to play a role in attention, vigilance, and cognition. H 3 receptor antagonists enhance the release of these neurotransmitters and, thus, may be potential human therapeutic agents for the treatment of disorders associated with attentional and cognitive deficits, such as attention deficit/hyperactivity disorder, Alzheimer's Disease, mild cognitive impairment, and schizophrenia (Leurs et al., 1998).Since the cloning of the human and rat H 3 receptors

Pharmacological Properties of ABT-239 [4-(2-{2-[(2R)-2-Methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile]: II. Neurophysiological Characterization and Broad Preclinical Efficacy in Cognition and Schizophrenia of a Potent and Selective Histamine H3 Receptor Antagonist

“…Indeed, the apparent loss of activity in social recognition at the highest dose may reflect a negative influence of ABT-239 at other H 3 heteroreceptors, producing a U-shaped dose response in this model. Taken together, it is possible that the observed improvement of social recognition memory with ABT-239 reflects enhanced acetylcholine and histamine release (for effects of ABT-239 on histamine release in rat brain cortical synaptosomes, see Esbenshade et al, 2005) in one or more of these key brain regions. ABT-239 was least potent and least efficacious in the water maze.…”

“…ABT-239 is a potent and selective antagonist and inverse agonist at H 3 Rs across several species, including rodent and human (see Esbenshade et al, 2005). A balanced affinity across species is important to allow assessment of the behavioral effects of selective blockade of H 3 Rs in preclinical and clinical studies.…”

Pharmacological Properties and Procognitive Effects of ABT-288, a Potent and Selective Histamine H3Receptor Antagonist

“…The reversal of (R)-␣-MeHA-mediated inhibition of EFS (test voltage ϳ7-8V; 0.1-Hz frequency; 0.5-ms duration) elicited twitches of guinea pig ileal segments by H 3 R antagonists was determined as described previously (Ireland-Denny et al, 2001;Esbenshade et al, 2005). Various concentrations of H 3 R antagonists were added to the tissue baths 30 min before the generation of (R)-␣-MeHA cumulative concentration response curves, and the potency (pA 2 ) of the antagonists to inhibit the (R)-␣-MeHA response was calculated according to the method of Schild (1947)) as described previously (Ireland-Denny et al, 2001;Esbenshade et al, 2005).…”

“…Various concentrations of H 3 R antagonists were added to the tissue baths 30 min before the generation of (R)-␣-MeHA cumulative concentration response curves, and the potency (pA 2 ) of the antagonists to inhibit the (R)-␣-MeHA response was calculated according to the method of Schild (1947)) as described previously (Ireland-Denny et al, 2001;Esbenshade et al, 2005).…”

“…The ability of H 3 R antagonists to reverse histamine-mediated inhibition of [ 3 H]histamine release from rat cerebral cortical synaptosomes evoked by potassium (15 mM) was determined as described previously (Arrang et al, 1985;Esbenshade et al, 2005). Synaptosomes (approximately 2 mg of protein) were added to microcentrifuge tubes containing 1 M of the agonist histamine (EC 50 ϭ 34 nM) either alone or together with ABT-288, and the mixture was incubated for 2 min at 37°C.…”