Ramin Faghih

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

Acute pharmacological blockade of central histamine H3 receptors (H3Rs) enhances arousal/attention in rodents. However, there is little information available for other behavioral domains or for repeated administration using selective compounds. ABT-239 [4-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile] exemplifies such a selective, nonimidazole H3R antagonist with high affinity for rat (pKi = 8.9) and human (pKi = 9.5) H3Rs. Acute functional blockade of central H3 Rs was demonstrated by blocking the dipsogenia response to the selective H3R agonist (R)-α-methylhistamine in mice. In cognition studies, acquisition of a five-trial, inhibitory avoidance test in rat pups was improved with ABT-239 (0.1–1.0 mg/kg), a 10- to 150-fold gain in potency, with similar efficacy, over previous antagonists such as thioperamide, ciproxifan, A-304121 [(4-(3-(4-((2R)-2-aminopropanoyl)-1-piperazinyl)propoxy)phenyl)(cyclopropyl) methanone], A-317920 [N-((1R)-2-(4-(3-(4-(cyclopropylcarbonyl) phenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethyl)-2-furamide], and A-349821 [(4′-(3-((R,R)2,5-dimethyl-pyrrolidin-1-yl)-propoxy)-biphenyl-4-yl)-morpholin-4-yl-methanone]. Efficacy in this model was maintained for 3 to 6 h and following repeated dosing with ABT-239. Social memory was also improved in adult (0.01–0.3 mg/kg) and aged (0.3–1.0 mg/kg) rats. In schizophrenia models, ABT-239 improved gating deficits in DBA/2 mice using prepulse inhibition of startle (1.0–3.0 mg/kg) and N40 (1.0–10.0 mg/kg). Furthermore, ABT-239 (1.0 mg/kg) attenuated methamphetamine-induced hyperactivity in mice. In freely moving rat microdialysis studies, ABT-239 enhanced acetylcholine release (0.1–3.0 mg/kg) in adult rat frontal cortex and hippocampus and enhanced dopamine release in frontal cortex (3.0 mg/kg), but not striatum. In summary, broad efficacy was observed with ABT-239 across animal models such that potential clinical efficacy may extend beyond disorders such as ADHD to include Alzheimers disease and schizophrenia.

Pharmacological Properties of ABT-239: II. Neurophysiological Characterization and Broad Preclinical Efficacy in Cognition and Schizophrenia of a Potent and Selective Histamine H3 Receptor Antagonist

Acute pharmacological blockade of central histamine H3 receptors (H3Rs) enhances arousal/attention in rodents. However, there is little information available for other behavioral domains or for repeated administration using selective compounds. ABT-239 [4-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile] exemplifies such a selective, nonimidazole H3R antagonist with high affinity for rat (pKi = 8.9) and human (pKi = 9.5) H3Rs. Acute functional blockade of central H3 Rs was demonstrated by blocking the dipsogenia response to the selective H3R agonist (R)-α-methylhistamine in mice. In cognition studies, acquisition of a five-trial, inhibitory avoidance test in rat pups was improved with ABT-239 (0.1–1.0 mg/kg), a 10- to 150-fold gain in potency, with similar efficacy, over previous antagonists such as thioperamide, ciproxifan, A-304121 [(4-(3-(4-((2R)-2-aminopropanoyl)-1-piperazinyl)propoxy)phenyl)(cyclopropyl) methanone], A-317920 [N-((1R)-2-(4-(3-(4-(cyclopropylcarbonyl) phenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethyl)-2-furamide], and A-349821 [(4′-(3-((R,R)2,5-dimethyl-pyrrolidin-1-yl)-propoxy)-biphenyl-4-yl)-morpholin-4-yl-methanone]. Efficacy in this model was maintained for 3 to 6 h and following repeated dosing with ABT-239. Social memory was also improved in adult (0.01–0.3 mg/kg) and aged (0.3–1.0 mg/kg) rats. In schizophrenia models, ABT-239 improved gating deficits in DBA/2 mice using prepulse inhibition of startle (1.0–3.0 mg/kg) and N40 (1.0–10.0 mg/kg). Furthermore, ABT-239 (1.0 mg/kg) attenuated methamphetamine-induced hyperactivity in mice. In freely moving rat microdialysis studies, ABT-239 enhanced acetylcholine release (0.1–3.0 mg/kg) in adult rat frontal cortex and hippocampus and enhanced dopamine release in frontal cortex (3.0 mg/kg), but not striatum. In summary, broad efficacy was observed with ABT-239 across animal models such that potential clinical efficacy may extend beyond disorders such as ADHD to include Alzheimers disease and schizophrenia.

Effects of histamine H3 receptor ligands GT-2331 and ciproxifan in a repeated acquisition avoidance response in the spontaneously hypertensive rat pup

Histamine H(3) receptor antagonists have been proposed as potentially useful therapeutic agents for the treatment of several disorders including attention deficit, schizophrenia, depression, and Alzheimers disease. We have developed a repeated acquisition version of an inhibitory avoidance task using spontaneously hypertensive rat (SHR) pups that we believe provides a reproducible measure of the cognitive and attention deficits often characteristic of these disease states, and evaluated two H(3) receptor antagonists. Male SHR, Wistar (WI) and Wistar Kyoto (WKY) rat pups (20--24 days old) were trained to avoid a mild footshock (0.1 mA, 1 s duration), delivered when the pup had transferred from a brightly lit to a darkened compartment. After the first trial, the pup was removed and returned to its home cage. One minute later, the same pup was replaced in the brightly-lit compartment and the training process repeated. A total of five trials were recorded. SHR pups performed significantly more poorly than WI or WKY pups using this training schedule, and SHR pups were used for all subsequent studies. Methylphenidate and ABT-418, both clinically active in attention deficit hyperactivity disorder (ADHD), were tested to validate the model. Methylphenidate (1 and 3 mg/kg s.c.) and ABT-418 (0.03 mg/kg s.c.) significantly improved SHR pup performance. The H(3) receptor antagonists GT-2331 (1 mg/kg s.c.) and ciproxifan (3 mg/kg s.c.), also significantly, and in a dose-related manner, enhanced performance of the SHR pups. (R)-alpha-methylhistamine (3 mg/kg s.c.) blocked the pro-cognitive effects of ciproxifan, suggesting an H(3) receptor site of action for this compound. This model is useful for evaluating the cognition/attention-enhancing potential of H(3) receptor antagonists.

Medicinal Chemistry and Biological Properties of Non-Imidazole Histamine H3 Antagonists

The H3 receptor is prominently expressed in neuronal tissues, and H3 antagonists have been proposed as drugs with benefits in disorders of cognition, attention, pain, allergic rhinitis, and obesity. The structure-activity relationships (SAR) of various classes of non-imidazole H3 antagonists are reviewed, along with highlights of functional efficacy in tissue-based and animal disease models.

Discovery of 4-(5-(4-Chlorophenyl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide (A-867744) as a Novel Positive Allosteric Modulator of the α7 Nicotinic Acetylcholine Receptor

The discovery of a series of pyrrole-sulfonamides as positive allosteric modulators (PAM) of alpha7 nAChRs is described. Optimization of this series led to the identification of 19 (A-867744), a novel type II PAM with good potency and selectivity. Compound 19 showed acceptable pharmacokinetic profile across species and brain levels sufficient to modulate alpha7 nAChRs. In a rodent model of sensory gating, 19 normalized gating deficits. These results suggest that 19 represents a novel class of molecules capable of allosteric modulation of the alpha7 nAChRs.

Aminoalkoxybiphenylnitriles as histamine-3 receptor ligands

Biaryl nitrile amines were prepared and found to have high affinity and selectivity for human and rat histamine H(3) receptors.

In Vitro Pharmacological Characterization of a Novel Allosteric Modulator of α7 Neuronal Acetylcholine Receptor, 4-(5-(4-Chlorophenyl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide (A-867744), Exhibiting Unique Pharmacological Profile

Targeting α7 neuronal acetylcholine receptors (nAChRs) with selective agonists and positive allosteric modulators (PAMs) is considered a therapeutic approach for managing cognitive deficits in schizophrenia and Alzheimers disease. In this study, we describe a novel type II α7 PAM, 4-(5-(4-chlorophenyl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide (A-867744), that exhibits a unique pharmacological profile. In oocytes expressing α7 nAChRs, A-867744 potentiated acetylcholine (ACh)-evoked currents, with an EC50 value of ∼1 μM. At highest concentrations of A-867744 tested, ACh-evoked currents were essentially nondecaying. At lower concentrations, no evidence of a distinct secondary component was evident in contrast to 4-naphthalen-1-yl-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonic acid amide (TQS), another type II α7 PAM. In the presence of A-867744, ACh concentration responses were potentiated by increases in potency, Hill slope, and maximal efficacy. When examined in rat hippocampus CA1 stratum radiatum interneurons or dentate gyrus granule cells, A-867744 (10 μM) increased choline-evoked α7 currents and recovery from inhibition/desensitization, and enhanced spontaneous inhibitory postsynaptic current activity. A-867744, like other α7 PAMs tested [1-(5-chloro-2-hydroxyphenyl)-3-(2-chloro-5-trifluoromethyl-phenyl)urea (NS1738), TQS, and 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl)-urea (PNU-120596)], did not displace the binding of [3H]methyllycaconitine to rat cortex α7* nAChRs. However, unlike these PAMs, A-867744 displaced the binding of the agonist [3H](1S,4S)-2,2-dimethyl-5-(6-phenylpyridazin-3-yl)-5-aza-2-azoniabicyclo[2.2.1]heptane (A-585539) in rat cortex, with a Ki value of 23 nM. A-867744 neither increased agonist-evoked responses nor displaced the binding of [3H]A-585539 in an α7/5-hydroxytryptamine3 (α7/5-HT3) chimera, suggesting an interaction distinct from the α7 N terminus or M2-3 loop. In addition, A-867744 failed to potentiate responses mediated by 5-HT3A or α3β4 and α4β2 nAChRs. In summary, this study identifies a novel and selective α7 PAM showing activity at recombinant and native α7 nAChRs exhibiting a unique pharmacological interaction with the receptor.

Lack of cataleptogenic potentiation with non-imidazole H3 receptor antagonists reveals potential drug-drug interactions between imidazole-based H3 receptor antagonists and antipsychotic drugs.

Since H3 receptor (H3R) antagonists/inverse agonists can improve cognitive function in animal models, they may have the potential to be used as add-on therapy in the treatment of schizophrenia, a disease with significant cognitive deficits. However, a recent study showed potentiation of haloperidol-induced catalepsy by ciproxifan, an imidazole-containing H3R antagonist/inverse agonist, suggesting there is a potential risk of exacerbating extrapyramidal symptoms (EPS) if H3R antagonists were used as adjunctive treatment [Pillot, C., Ortiz, J., Heron, A., Ridray, S., Schwartz, J.C. and Arrang, J.M., Ciproxifan, a histamine H3-receptor antagonist/inverse agonist, potentiates neurochemical and behavioral effects of haloperidol in the rat, J Neurosci, 22 (2002) 7272-80]. In order to clarify the basis of this finding, we replicated this result and extended the work with another imidazole and two non-imidazole H3R antagonists. The results indicate that ciproxifan significantly augmented the effects of haloperidol and risperidone on catalepsy. Another imidazole H3R antagonist, thioperamide, also potentiated the effect of risperidone on catalepsy. In contrast, no catalepsy-enhancing effects were observed when selective non-imidazole H3R antagonists, ABT-239 and A-431404, were coadministered with haloperidol and/or risperidone. As ciproxifan and thioperamide are inhibitors of cytochrome P450 enzymes, responsible for metabolizing risperidone and haloperidol, the possibility that the augmentation of antipsychotics by imidazoles resulted from drug-drug interactions was tested. A drug metabolism study revealed that an imidazole, but not a non-imidazole, potently inhibited the metabolism of haloperidol and risperidone. Furthermore, ketoconazole, an imidazole-based CYP 3A4 inhibitor, significantly augmented risperidone-induced catalepsy. Together, these data suggest the potentiation of antipsychotic-induced catalepsy may result from pharmacokinetic drug-drug interactions and support the potential utility of non-imidazole H3R antagonists in treatment of cognitive impairment in schizophrenia without increased risk of increased EPS in patients.

Advances in the Discovery of Novel Positive Allosteric Modulators of the α7 Nicotinic Acetylcholine Receptor

The alpha7 subtype of the nicotinic acetylcholine receptor (nAChR) is a target of considerable interest in CNS drug discovery, in part due to its implication in diseases of unmet medical need such as schizophrenia and Alzheimers disease. Pharmacological distinction of this subtype from other nAChRs is exemplified by antagonists such as alpha-bungarotoxin and methyllycaconitine, and more recently by agonists that have emerged from various structural classes. Increasing evidence, both preclinical and clinical, has also demonstrated that alpha7 nAChR agonists and partial agonists can lead to improvements in cognitive performance. An attractive alternative approach to modulating alpha7 nAChR function is to enhance the effects of the endogenous neurotransmitter acetylcholine (ACh) through positive allosteric modulation (PAM). This class of compounds - positive allosteric modulators (PAMs) - could selectively modulate the activity of ACh at alpha7 nAChRs in a manner that may have significant advantages over indiscriminate and direct activation of nAChRs by nicotine/nicotinic agonists or by acetylcholinesterase inhibitors. Validation of the alpha7 nAChR-selective PAM approach requires the identification of potent and selective compounds. Initially identified nAChR allosteric modulators, including 5-hydroxyindole (5-HI), galantamine, bovine serum albumin, and SLURP-1, are weak and nonselective. More recently, potent and alpha7 nAChR-selective PAMs belonging to diverse chemotypes have emerged and are beginning to be optimized as tools for concept validation in preclinical models and in the clinic. This review summarizes the current status of nAChR-selective PAMs, from patents and published literature, and their potential for the treatment of cognitive deficits associated with neuropsychiatric and neurodegenerative disorders and other diseases.

Differential in vivo effects of H3 receptor ligands in a new mouse dipsogenia model.

The selective H(3) receptor agonist (R)-alpha-methylhistamine [(R)-alpha-MeHA] stimulates drinking in the adult rat. In the present study, we investigated the role of the H(3) receptor in mediating this behavior in a new dipsogenia model using the CD-1 mouse. In addition, the putative inverse agonists ciproxifan, thioperamide and clobenpropit; the reported antagonist (1R,2R)-4-[2-(5,5-dimethylhex-1-ynyl)cyclopropyl]imidazole (GT-2331); and the putative neutral antagonist/weak partial agonist proxyfan were evaluated for possible differences in pharmacological activity in this new model. Water intake increased over baseline in a dose-related manner following intraperitoneal administration of 80, 160 or 240 micromol/kg (R)-alpha-MeHA, but this effect was dependent on age (P30<P60<P80=P120). [3H]-N-alpha-methylhistamine binding studies showed no change in H(3) receptor density for the whole mouse brain at these ages. All subsequent studies employed P80 mice dosed with 240 micromol/kg (R)-alpha-MeHA. Ciproxifan (0.001-30 micromol/kg), thioperamide (0.01-10 micromol/kg), clobenpropit (0.1-30 micromol/kg) and GT-2331 (0.03-10 micromol/kg) attenuated drinking dose-dependently, blocking the response completely at the highest doses in each case. In contrast, proxyfan (0.001-10 micromol/kg) only partially attenuated drinking elicited by (R)-alpha-MeHA: coadministration of proxyfan and ciproxifan resulted in an attenuation of ciproxifans effects. This new dipsogenia model provides the first in vivo behavioral evidence for possible pharmacological differences between three putative H(3) receptor inverse agonists, GT-2331 and proxyfan.