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1.
J Med Chem ; 52(10): 3377-84, 2009 May 28.
Article in English | MEDLINE | ID: mdl-19419141

ABSTRACT

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.


Subject(s)
Allosteric Regulation , Pyrroles/pharmacology , Receptors, Nicotinic/drug effects , Sensory Gating/drug effects , Sulfonamides/pharmacology , Animals , Brain/metabolism , Cells, Cultured , Drug Discovery , Mice , Microsomes , Oocytes , Patch-Clamp Techniques , Pharmacokinetics , Xenopus laevis , alpha7 Nicotinic Acetylcholine Receptor , Benzenesulfonamides
2.
J Pharmacol Exp Ther ; 330(1): 257-67, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19389923

ABSTRACT

Targeting alpha7 neuronal acetylcholine receptors (nAChRs) with selective agonists and positive allosteric modulators (PAMs) is considered a therapeutic approach for managing cognitive deficits in schizophrenia and Alzheimer's disease. In this study, we describe a novel type II alpha7 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 alpha7 nAChRs, A-867744 potentiated acetylcholine (ACh)-evoked currents, with an EC(50) value of approximately 1 microM. 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 alpha7 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 microM) increased choline-evoked alpha7 currents and recovery from inhibition/desensitization, and enhanced spontaneous inhibitory postsynaptic current activity. A-867744, like other alpha7 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 [(3)H]methyllycaconitine to rat cortex alpha7(*) nAChRs. However, unlike these PAMs, A-867744 displaced the binding of the agonist [(3)H](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 K(i) value of 23 nM. A-867744 neither increased agonist-evoked responses nor displaced the binding of [(3)H]A-585539 in an alpha7/5-hydroxytryptamine(3) (alpha7/5-HT(3)) chimera, suggesting an interaction distinct from the alpha7 N terminus or M2-3 loop. In addition, A-867744 failed to potentiate responses mediated by 5-HT(3A) or alpha3beta4 and alpha4beta2 nAChRs. In summary, this study identifies a novel and selective alpha7 PAM showing activity at recombinant and native alpha7 nAChRs exhibiting a unique pharmacological interaction with the receptor.


Subject(s)
Pyrroles/chemistry , Pyrroles/pharmacology , Receptors, Nicotinic/metabolism , Sulfonamides/chemistry , Sulfonamides/pharmacology , Allosteric Regulation/drug effects , Allosteric Regulation/physiology , Animals , Cell Line , Cholinergic Agents/chemistry , Cholinergic Agents/pharmacology , Dose-Response Relationship, Drug , Female , Humans , Male , Rats , Rats, Sprague-Dawley , Xenopus laevis , alpha7 Nicotinic Acetylcholine Receptor , Benzenesulfonamides
4.
Biochem Pharmacol ; 73(8): 1243-55, 2007 Apr 15.
Article in English | MEDLINE | ID: mdl-17371699

ABSTRACT

Three novel heterocyclic benzofurans A-688057 (1), A-687136 (2), and A-698418 (3) were profiled for their in vitro and in vivo properties as a new series of histamine H(3) receptor antagonists. The compounds were all found to have nanomolar potency in vitro at histamine H(3) receptors, and when profiled in vivo for CNS activity, all were found active in an animal behavioral model of attention. The compound with the most benign profile versus CNS side effects was selected for greater scrutiny of its in vitro properties and overall drug-likeness. This compound, A-688057, in addition to its potent and robust efficacy in two rodent behavioral models at blood levels ranging 0.2-19 nM, possessed other favorable features, including high selectivity for H(3) receptors (H(3), K(i)=1.5 nM) versus off-target receptors and channels (including the hERG K(+) channel, K(i)>9000 nM), low molecular weight (295), high solubility, moderate lipophilicity (logD(pH7.4)=2.05), and good CNS penetration (blood/brain 3.4x). In vitro toxicological tests indicated low potential for phospholipidosis, genotoxicity, and CYP(450) inhibition. Even though pharmacokinetic testing uncovered only moderate to poor oral bioavailability in rat (26%), dog (30%), and monkey (8%), and only moderate blood half-lives after i.v. administration (t(1/2) in rat of 2.9h, 1.7h in dog, 1.8h in monkey), suggesting poor human pharmacokinetics, the data overall indicated that A-688057 has an excellent profile for use as a pharmacological tool compound.


Subject(s)
Behavior, Animal/drug effects , Histamine Antagonists/pharmacology , Receptors, Histamine H3/physiology , Animals , Behavior, Animal/physiology , Benzofurans/chemistry , Benzofurans/pharmacology , Dogs , Haplorhini , Histamine Antagonists/blood , Humans , Rats , Receptors, Histamine H3/drug effects
5.
Recent Pat CNS Drug Discov ; 2(2): 99-106, 2007 Jun.
Article in English | MEDLINE | ID: mdl-18221220

ABSTRACT

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 Alzheimer's 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.


Subject(s)
Drug Design , Nicotinic Agonists/pharmacology , Receptors, Nicotinic/drug effects , Allosteric Regulation , Animals , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Cognition Disorders/drug therapy , Humans , Nicotinic Agonists/therapeutic use , Quinolines/pharmacology , Thiazoles/pharmacology , Urea/pharmacology , alpha7 Nicotinic Acetylcholine Receptor
6.
Br J Pharmacol ; 148(5): 657-70, 2006 Jul.
Article in English | MEDLINE | ID: mdl-16715122

ABSTRACT

1. A-349821 is a selective histamine H3 receptor antagonist/inverse agonist. Herein, binding of the novel non-imidazole H3 receptor radioligand [3H]A-349821 to membranes expressing native or recombinant H3 receptors from rat or human sources was characterized and compared with the binding of the agonist [3H]N--methylhistamine ([3H]NMH). 2. [3H]A-349821 bound with high affinity and specificity to an apparent single class of saturable sites and recognized human H3 receptors with 10-fold higher affinity compared to rat H3 receptors. [3H]A-349821 detected larger populations of receptors compared to [3H]NMH. 3. Displacement of [3H]A-349821 binding by H3 receptor antagonists/inverse agonists was monophasic, suggesting recognition of a single binding site, while that of H3 receptor agonists was biphasic, suggesting recognition of both high- and low-affinity H3 receptor sites. 4. pKi values of high-affinity binding sites for H3 receptor competitors utilizing [3H]A-349821 were highly correlated with pKi values obtained with [3H]NalphaMH, consistent with labelling of H3 receptors by [3H]A-349821. 5. Unlike assays utilizing [3H]NMH, addition of GDP had no effect on saturation parameters measured with [3H]A-349821, while displacement of [3H]A-349821 binding by the H3 receptor agonist histamine was sensitive to GDP. 6. In conclusion, [3H]A-349821 labels interconvertible high- and low-affinity states of the H3 receptor, and displays improved selectivity over imidazole-containing H3 receptor antagonist radioligands. [3H]A-349821 competition studies showed significant differences in the proportions and potencies of high- and low-affinity sites across species, providing new information about the fundamental pharmacological nature of H3 receptors.


Subject(s)
Biphenyl Compounds/pharmacokinetics , Histamine Antagonists/pharmacology , Radioligand Assay/methods , Receptors, Histamine H3/chemistry , Receptors, Histamine H3/metabolism , Animals , Binding, Competitive/drug effects , Cells, Cultured , Guanosine Diphosphate/pharmacology , Histamine/pharmacology , Histamine Agonists/pharmacology , Humans , Imidazoles/pharmacology , Methylhistamines/pharmacology , Models, Biological , Protein Binding/drug effects , Rats , Thiourea/analogs & derivatives , Thiourea/pharmacology
7.
J Med Chem ; 48(20): 6482-90, 2005 Oct 06.
Article in English | MEDLINE | ID: mdl-16190774

ABSTRACT

A new series of H3 receptor antagonists was discovered with nanomolar and subnanomolar affinities at human and rat H3 receptors. Starting from an earlier, more structurally limited series of benzofurans, the present series of compounds demonstrated increased structural variety and flexibility with greater in vitro potency. One compound in particular, [2-[2-(2-(R)-methylpyrrolidin-1-yl)ethyl]benzofuran-5-yl](5-nitropyridin-2-yl)amine (7h), gave the best binding potency (human K(i) of 0.05 nM, rat K(i) of 0.11 nM), which represented a 9-fold (in human) and an 11-fold (in rat) improvement over ABT-239 (compound 5), a compound previously reported to have excellent in vitro potency and in vivo efficacy. The synthesis, SAR of the H3 binding affinities, in vitro assay for phospholipidosis, and pharmacokinetic properties of the new compounds are described.


Subject(s)
Benzofurans/chemical synthesis , Histamine Antagonists/chemical synthesis , Pyrrolidines/chemical synthesis , Receptors, Histamine H3/drug effects , Animals , Benzofurans/pharmacokinetics , Benzofurans/pharmacology , Cells, Cultured , Hepatocytes/drug effects , Hepatocytes/metabolism , Histamine Antagonists/pharmacokinetics , Histamine Antagonists/pharmacology , Humans , Male , Phospholipids/biosynthesis , Pyrrolidines/pharmacokinetics , Pyrrolidines/pharmacology , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptors, Histamine H3/metabolism , Structure-Activity Relationship
9.
Brain Res ; 1045(1-2): 142-9, 2005 May 31.
Article in English | MEDLINE | ID: mdl-15910772

ABSTRACT

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.


Subject(s)
Antipsychotic Agents/pharmacokinetics , Brain Chemistry/drug effects , Cataplexy/chemically induced , Histamine Antagonists/pharmacokinetics , Histamine/metabolism , Receptors, Histamine H3/drug effects , Animals , Antipsychotic Agents/adverse effects , Benzofurans/chemistry , Benzofurans/pharmacokinetics , Brain Chemistry/physiology , Cataplexy/physiopathology , Cataplexy/prevention & control , Cytochrome P-450 Enzyme System/drug effects , Cytochrome P-450 Enzyme System/metabolism , Drug Combinations , Drug Synergism , Haloperidol/pharmacokinetics , Histamine Antagonists/chemistry , Imidazoles/chemistry , Imidazoles/pharmacokinetics , Ketoconazole/pharmacokinetics , Male , Metabolic Clearance Rate/drug effects , Metabolic Clearance Rate/physiology , Piperidines/chemistry , Piperidines/pharmacokinetics , Pyrrolidines/chemistry , Pyrrolidines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Receptors, Histamine H3/metabolism , Risperidone/pharmacokinetics , Schizophrenia/drug therapy
10.
J Med Chem ; 48(1): 38-55, 2005 Jan 13.
Article in English | MEDLINE | ID: mdl-15634000

ABSTRACT

H(3) receptor antagonists based on a 2-aminoethylbenzofuran skeleton have been discovered, which are potent in vitro at human and rat H(3) receptors, with K(i) values of 0.1-5.8 nM. Analogues were discovered with potent (0.01-1 mg/kg) cognition and attention enhancing properties in animal models. One compound in particular, 4-(2-[2-(2(R)-methylpyrrolidin-1-yl)ethyl]benzofuran-5-yl)benzonitrile (ABT-239), combined potent and selective H(3) receptor antagonism and excellent pharmacokinetic and metabolic properties across species, with full efficacy in two behavioral models: a five-trial inhibitory avoidance acquisition model in rat pups at 0.1 mg/kg and a social recognition memory model in adult rats at 0.01 mg/kg. Furthermore, this compound did not stimulate locomotor activity and showed high selectivity for the induction of behavioral efficacy versus central nervous system based side effects. The potency and selectivity of this compound and of analogues from this class support the potential of H(3) receptor antagonists for the treatment of cognitive dysfunction.


Subject(s)
Attention/drug effects , Benzofurans/pharmacology , Cognition/drug effects , Histamine Antagonists/pharmacology , Pyrrolidines/pharmacology , Receptors, Histamine H3/drug effects , Administration, Oral , Animals , Avoidance Learning/drug effects , Behavior, Animal/drug effects , Benzofurans/chemistry , Biological Availability , Blood Proteins/metabolism , Central Nervous System/drug effects , Central Nervous System Agents/chemistry , Central Nervous System Agents/pharmacology , Cytochrome P-450 Enzyme System/drug effects , Dogs , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical/methods , Haplorhini , Histamine Antagonists/chemistry , Histamine Antagonists/pharmacokinetics , Humans , Memory/drug effects , Pyrrolidines/chemistry , Rats , Social Behavior , Structure-Activity Relationship
11.
J Pharmacol Exp Ther ; 313(1): 176-90, 2005 Apr.
Article in English | MEDLINE | ID: mdl-15608077

ABSTRACT

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 (pK(i) = 8.9) and human (pK(i) = 9.5) H3Rs. Acute functional blockade of central H3Rs was demonstrated by blocking the dipsogenia response to the selective H3R agonist (R)-alpha-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 Alzheimer's disease and schizophrenia.


Subject(s)
Benzofurans/pharmacology , Benzofurans/therapeutic use , Cognition Disorders/drug therapy , Histamine Antagonists/pharmacology , Histamine Antagonists/therapeutic use , Pyrrolidines/pharmacology , Pyrrolidines/therapeutic use , Receptors, Histamine H3/drug effects , Schizophrenia/drug therapy , Aging/psychology , Animals , Avoidance Learning/drug effects , Benzofurans/administration & dosage , Central Nervous System Stimulants , Cognition Disorders/psychology , Dose-Response Relationship, Drug , Drinking/drug effects , Electroencephalography/drug effects , Histamine Antagonists/administration & dosage , Hyperkinesis/chemically induced , Hyperkinesis/prevention & control , Male , Maze Learning/drug effects , Methamphetamine , Mice , Mice, Inbred DBA , Microdialysis , Neurons/drug effects , Neurons/metabolism , Neurotransmitter Agents/metabolism , Pyrrolidines/administration & dosage , Rats , Rats, Inbred SHR , Reflex, Startle/drug effects , Social Behavior
12.
Mini Rev Med Chem ; 4(9): 979-92, 2004 Nov.
Article in English | MEDLINE | ID: mdl-15544558

ABSTRACT

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.


Subject(s)
Histamine Antagonists/chemistry , Histamine Antagonists/pharmacology , Receptors, Histamine H3/metabolism , Animals , Benzofurans/chemistry , Histamine Antagonists/therapeutic use , Humans , Imidazoles/chemistry , Structure-Activity Relationship
13.
Basic Clin Pharmacol Toxicol ; 95(3): 144-52, 2004 Sep.
Article in English | MEDLINE | ID: mdl-15447739

ABSTRACT

A-331440 [4'-[3-(3(R)-(dimethylamino)-pyrrolidin-1-yl)-propoxy]-biphenyl-4-carbonitrile], a potent and selective antagonist of histamine H3 receptors, yielded positive results in an in vitro micronucleus assay, predictive of genotoxicity in vivo. Because this compound has highly favourable properties and potential as an antiobesity agent, new compounds of this general chemical class were sought that would retain or improve upon the high potency and selectivity of A-331440 for H3 receptors, but would lack the potential for genotoxicity obtained with that compound. Our working hypothesis was that the biphenyl rings in A-331440 might contribute to interactions with DNA and thereby predispose toward genotoxicity. Toward this end, several analogues were prepared, with substituents introduced onto the biaryl ring to alter the orientation, electronegativity, and polarity of this moiety, and were tested for their radioligand binding potency and selectivity and their propensity to induce genotoxicity in the in vitro micronucleus assay. Using this strategy, novel compounds were discovered that retained or improved upon the potency and selectivity of A-331440 for H3 receptors and were devoid of genotoxicity in vitro. Of these, the simple mono- and di-fluorinated analogues (A-417022 [4'-[3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy]-3'-fluoro-1,1'-biphenyl-4-carbonitrile] and A-423579 [4'-[3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]-propoxy]-3',5'-difluoro-1,1'-biphenyl-4-carbonitrile], respectively) were found to bind to H3 receptors at least as potently as A-331440, while lacking genotoxicity in the micronucleus assay. The reason of the lack of genotoxicity of the fluorinated analogues is unclear, but is especially noteworthy in light of the general principle that fluorine and hydrogen are very similar in size. Therefore, these fluorinated analogues of A-331440 represented the most potent and potentially safest compounds for further evaluation as antiobesity leads. Preliminary findings with one of these examples, A-417022, in a mouse model of obesity are presented.


Subject(s)
Anti-Obesity Agents/pharmacology , Biphenyl Compounds/pharmacology , Histamine Antagonists/pharmacology , Nitriles/pharmacology , Pyrrolidines/pharmacology , Receptors, Histamine H3/metabolism , Animals , Cell Line , Cricetinae , Cricetulus , Disease Models, Animal , Drug Design , Histamine Antagonists/chemical synthesis , Mice , Mice, Inbred C57BL , Micronucleus Tests , Molecular Structure , Radioligand Assay , Structure-Activity Relationship , Weight Loss/drug effects
14.
Biochem Pharmacol ; 68(5): 933-45, 2004 Sep 01.
Article in English | MEDLINE | ID: mdl-15294456

ABSTRACT

Histamine H3 receptors regulate the release of a variety of central neurotransmitters involved in cognitive processes. A-349821 ((4'-(3-((R,R)2,5-dimethyl-pyrrolidin-1-yl)-propoxy)-biphenyl-4-yl)-morpholin-4-yl-methanone) is a novel, non-imidazole H3 receptor ligand, displaying high affinity for recombinant rat and human H3 receptors, with pKi values of 9.4 and 8.8, respectively, and high selectivity for the H3 receptor versus H1, H2, and H4 histamine receptors. A-349821 is a potent H3 receptor antagonist in a variety of models using recombinant human and rat receptors, reversing agonist induced changes in cyclic AMP formation (pKb= 8.2 and pKb= 8.1, respectively), [35S]-GTPgammaS binding (pKb= 9.3 and pKb= 8.6, respectively) and calcium levels (human pKb= 8.3). In native systems, A-349821 competitively reversed agonist induced inhibition of electric field stimulated guinea-pig ileum (pA2= 9.5) and histamine-mediated inhibition of [3H]-histamine release from rat brain cortical synaptosomes (pKb= 9.2). Additionally, A-349821 inhibited constitutive GTPgammaS binding at both rat and human H3 receptors with respective pEC50 values of 9.1 and 8.6, demonstrating potent inverse agonist properties. In behavioral studies, A-349821 (0.4 mg/kg-4 mg/kg) potently blocked (R)-alpha-methylhistamine-induced dipsogenia in mice. The compound also enhanced cognitive activity in a five-trial inhibitory avoidance model in spontaneously hypertensive rat (SHR) pups at doses of 1-10mg/kg, with the 1mg/kg dose showing comparable efficacy to a fully efficacious dose of ciproxifan (3mg/kg). These doses of A-349821 were without effect on spontaneous locomotor activity. Thus, A-349821 is a novel, selective non-imidazole H3 antagonist/inverse agonist with balanced high potency across species and favorable cognition enhancing effects in rats.


Subject(s)
Biphenyl Compounds/pharmacology , Histamine Antagonists/pharmacology , Histamine/metabolism , Receptors, Histamine H3/metabolism , Animals , Avoidance Learning/drug effects , Dogs , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Guinea Pigs , Humans , Male , Motor Activity/drug effects , Neurotransmitter Agents/metabolism , Rats , Rats, Inbred SHR , Rats, Sprague-Dawley , Receptors, Histamine H3/genetics , Recombinant Proteins/antagonists & inhibitors , Sulfur Radioisotopes
15.
Arch Pharm (Weinheim) ; 337(4): 219-29, 2004 Apr.
Article in English | MEDLINE | ID: mdl-15146898

ABSTRACT

Structure-activity relationships of homopiperazine-containing alkoxybiaryl nitriles employing various D-amino acid moieties and their N-furanoyl analogues were undertaken. This led to A-320436, a potent and selective non-imidazole H(3)-receptor antagonist possessing balanced affinity for both rat and human H(3)-receptors. This compound was shown to demonstrate in vitro and in vivo functional antagonism and is non-neurotoxic at doses (i.p.) up to 163 mg/kg in a general observation test.


Subject(s)
Histamine Antagonists/chemical synthesis , Piperazines/chemical synthesis , Receptors, Histamine H3/drug effects , Animals , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Histamine Antagonists/chemistry , Histamine Antagonists/pharmacology , Humans , Mice , Piperazines/chemistry , Piperazines/pharmacology , Rats , Receptors, Histamine H3/metabolism , Structure-Activity Relationship
16.
Eur J Pharmacol ; 487(1-3): 183-97, 2004 Mar 08.
Article in English | MEDLINE | ID: mdl-15033391

ABSTRACT

Histamine affects homeostatic mechanisms, including food and water consumption, by acting on central nervous system (CNS) receptors. Presynaptic histamine H(3) receptors regulate release of histamine and other neurotransmitters, and histamine H(3) receptor antagonists enhance neurotransmitter release. A-331440 [4'-[3-(3(R)-(dimethylamino)-pyrrolidin-1-yl)-propoxy]-biphenyl-4-carbonitrile] is a histamine H(3) receptor antagonist which binds potently and selectively to both human and rat histamine H(3) receptors (K(i)<==25 nM). Mice were stabilized on a high-fat diet (45 kcal % lard) prior to 28-day oral b.i.d. dosing for measurement of obesity-related parameters. A-331440 administered at 0.5 mg/kg had no significant effect on weight, whereas 5 mg/kg decreased weight comparably to dexfenfluramine (10 mg/kg). A-331440 administered at 15 mg/kg reduced weight to a level comparable to mice on the low-fat diet. The two higher doses reduced body fat and the highest dose also normalized an insulin tolerance test. These data show that the histamine H(3) receptor antagonist, A-331440, has potential as an antiobesity agent.


Subject(s)
Anti-Obesity Agents/pharmacology , Biphenyl Compounds/pharmacology , Histamine Antagonists/pharmacology , Nitriles/pharmacology , Pyrrolidines/pharmacology , Receptors, Histamine H3/drug effects , Adipose Tissue/drug effects , Animals , Appetite Depressants/pharmacology , Behavior, Animal/drug effects , Body Composition/drug effects , Body Weight/drug effects , Calcium/metabolism , Cloning, Molecular , Diagnostic Imaging , Diet , Dietary Fats/pharmacology , Fenfluramine/pharmacology , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Humans , Magnetic Resonance Imaging , Mice , Mice, Inbred C57BL , Radioligand Assay , Rats , Weight Loss/drug effects
19.
J Pharmacol Exp Ther ; 305(3): 897-908, 2003 Jun.
Article in English | MEDLINE | ID: mdl-12606600

ABSTRACT

Pharmacological blockade of central histamine H3 receptors (H3Rs) enhances cognition in rodents and offers promise for the clinical treatment of neurological disorders. However, many previously characterized H3R antagonists are either not selective for H3Rs or have potentially significant tolerability issues. Here, we present in vivo behavioral and neurophysiological data for two novel and selective H3R antagonists with improved safety indices. Functional blockade of central H3Rs was first demonstrated for A-304121 [(4-(3-(4-((2R)-2-aminopropanoyl)-1-piperazinyl)propoxy)phenyl)cyclopropylmethanone] (1 mg/kg) and A-317920 [N-((1R)-2-(4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxo-ethyl)-2-furamide] (0.45 mg/kg) by significantly attenuating an acute dipsogenia response to the selective H3R agonist (R)-alpha-methylhistamine [(R)-alpha-MeHA]. Cognitive performance was improved in a five-trial rat pup avoidance test following administration of A-304121 (10 mg/kg) or A-317920 (3 mg/kg), with efficacy comparable with previously published observations for reference H3R antagonists thioperamide (10 mg/kg), ciproxifan (3 mg/kg), and GT-2331 [(1R,2R)-4-(2-(5,5-dimethylhex-1-ynyl)cyclopropyl)imidazole] (1 mg/kg). Social memory was also significantly enhanced in the adult rat with A-304121 (3, 10 mg/kg) and A-317920 (1, 3 mg/kg) at doses that produced no significant change in electroencephalogram slow-wave amplitude activity. Relative therapeutic indices (TIs) of 30 and 42 were estimated for A-304121 and A-317920, respectively, by comparing doses producing adverse effects in general observation studies with potency in inhibitory avoidance, which were superior to TIs of 8, 10, and 18 observed for the reference antagonists thioperamide, ciproxifan, and GT-2331, respectively. A-304121 and A-317920 represent a series of novel, H3R-selective piperazine amides that enhance cognition in vivo, which could offer advantages over existing H3R antagonists or cognition-enhancing agents.


Subject(s)
Avoidance Learning/drug effects , Histamine Antagonists/pharmacology , Motor Activity/drug effects , Piperazines/pharmacology , Analysis of Variance , Animals , Electroencephalography/drug effects , Memory/drug effects , Mice , Rats , Rats, Inbred SHR , Receptors, Histamine H3/metabolism
20.
J Pharmacol Exp Ther ; 305(3): 887-96, 2003 Jun.
Article in English | MEDLINE | ID: mdl-12606603

ABSTRACT

Histamine H3 receptor (H3R) antagonists enhance neurotransmitter release and are being developed for the treatment of a variety of neurological and cognitive disorders. Many potent histamine H3R antagonists contain an imidazole moiety that limits receptor selectivity and the tolerability of this class of compounds. Here we present the in vitro pharmacological data for two novel piperazine amide ligands, A-304121 [4-(3-((2R)-2-aminopropanoyl-1-piperazinyl)propoxy)phenyl)cyclopropylmethanone] and A-317920 [N-((1R)-2-(4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxo-ethyl-)-2-furamide], and compare them with the imidazole H3R antagonists ciproxifan, clobenpropit, and thioperamide. Both A-304121 and A-317920 bind potently to recombinant full-length rat H3R(pKi values = 8.6 and 9.2, respectively) but have lower potencies for binding the full-length human H3R (pKi values = 6.1 and 7.0, respectively). A-304121 and A-317920 are potent antagonists at rat H3R in reversing R-alpha-methylhistamine [(R)-alpha-MeHA] inhibition of forskolin-stimulated cAMP formation (pKb values = 8.0 and 9.1) but weak antagonists at human H3Rs in cyclase (pKb values = 6.0 and 6.3) and calcium mobilization (pKb values = 6.0 and 7.3) assays in cells co-expressing Galphaqi5-protein. Both compounds potently antagonize native H3Rs by blocking histamine inhibition of potassium-evoked [3H]histamine release from rat brain cortical synaptosomes (pKb values = 8.6 and 9.3) and (R)-alpha-MeHA reversal of electric field-stimulated guinea pig ileum contractions (pA2 values = 7.1 and 8.3). A-304121 and A-317920 are also more efficacious inverse agonists in reversing basal guanosine 5'-O-(3-[35S]thio)triphosphate ([35S]GTP gamma S) binding at the human H3R (pEC50 values = 5.7 and 7.0) than are the imidazole antagonists. These novel and selective piperazine amides represent useful leads for the development of H3R antagonist therapeutic agents.


Subject(s)
Histamine Antagonists/pharmacology , Piperazines/pharmacology , Receptors, Histamine H3/metabolism , Animals , Binding Sites , Dose-Response Relationship, Drug , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Humans , Male , Neurotransmitter Agents/metabolism , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptors, Histamine H3/drug effects , Recombinant Proteins/drug effects , Recombinant Proteins/metabolism , Sulfur Radioisotopes
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