ABSTRACT
The preclinical characterization of novel phenyl(piperazin-1-yl)methanones that are histamine H3 receptor antagonists is described. The compounds described are high affinity histamine H3 antagonists. Optimization of the physical properties of these histamine H3 antagonists led to the discovery of several promising lead compounds, and extensive preclinical profiling aided in the identification of compounds with optimal duration of action for wake promoting activity. This led to the discovery of two development candidates for Phase I and Phase II clinical trials.
ABSTRACT
A novel alpha 7 nAChR agonist, 4-(5-methyloxazolo[4,5-b]pyridin-2-yl)-1,4-diazabicyclo[3.2.2]nonane (24, CP-810,123), has been identified as a potential treatment for cognitive deficits associated with psychiatric or neurological conditions including schizophrenia and Alzheimer's disease. Compound 24 is a potent and selective compound with excellent pharmaceutical properties. In rodent, the compound displays high oral bioavailability and excellent brain penetration affording high levels of receptor occupancy and in vivo efficacy in auditory sensory gating and novel object recognition. The structural diversity of this compound and its preclinical in vitro and in vivo package support the hypothesis that alpha 7 nAChR agonists may have potential as a pharmacotherapy for the treatment of cognitive deficits in schizophrenia.
Subject(s)
Azabicyclo Compounds/chemical synthesis , Azabicyclo Compounds/pharmacology , Cognition Disorders/drug therapy , Nicotinic Agonists/chemical synthesis , Nicotinic Agonists/pharmacology , Nootropic Agents/chemical synthesis , Nootropic Agents/pharmacology , Oxazoles/chemical synthesis , Oxazoles/pharmacology , Receptors, Nicotinic/chemistry , Schizophrenia/drug therapy , Animals , Azabicyclo Compounds/chemistry , Biological Availability , Cells, Cultured , Epithelial Cells/drug effects , Female , Hippocampus/drug effects , Humans , Kidney/cytology , Kidney/drug effects , Microsomes, Liver/drug effects , Nicotinic Agonists/chemistry , Nootropic Agents/chemistry , Oocytes/drug effects , Oxazoles/chemistry , Rats , Skin/cytology , Skin/drug effects , Structure-Activity Relationship , Xenopus laevis/growth & development , alpha7 Nicotinic Acetylcholine ReceptorABSTRACT
The synthesis and SAR studies about the bicyclic amine, carbamate linker and aromatic ring of a 1,4-diazabicyclo[3.2.2]nonane phenyl carbamate series of alpha7 nAChR agonists is described. The development of the medicinal chemistry strategy and SAR which led to the identification of 5 and 7aa as subtype selective, high affinity alpha7 agonists as excellent leads for further evaluation is discussed, along with key physicochemical and pharmacokinetic data highlighting their lead potential.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Carbamates/chemical synthesis , Nicotinic Agonists/chemical synthesis , Phenylcarbamates/chemical synthesis , Receptors, Nicotinic/chemistry , Animals , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Carbamates/chemistry , Carbamates/pharmacokinetics , Cell Line , Humans , Male , Nicotinic Agonists/chemistry , Nicotinic Agonists/pharmacokinetics , Phenylcarbamates/chemistry , Phenylcarbamates/pharmacokinetics , Rats , Rats, Sprague-Dawley , Receptors, Nicotinic/metabolism , Structure-Activity Relationship , alpha7 Nicotinic Acetylcholine ReceptorABSTRACT
In a two-year carcinogenicity study with administration of high doses of the partial nicotinic agonist varenicline (recently approved for smoking cessation), mediastinal hibernomas occurred in three male rats. To investigate potential mechanisms for partial and full nicotinic agonists to contribute to development of hibernomas, the effects of nicotine on rat brown adipose tissue (BAT) were studied. Male and female rats were administered nicotine at doses of 0, 0.3, and 1 mg/kg subcutaneously for fourteen days. Intrathoracic (mediastinal periaortic and mediastinal perithymic) BAT and interscapular BAT were examined microscopically, and determinations of uncoupling protein-1 (UCP-1) expression and norepinephrine (NE) content were made. Additionally, NE turnover was measured in mediastinal periaortic and perithymic BAT. Nicotine (1 mg/kg) administration resulted in decreased vacuolation only in mediastinal periaortic and mediastinal perithymic BAT of males and elevated UCP-1 in mediastinal periaortic BAT of males and females. Increased NE content occurred only in mediastinal periaortic BAT of males given 0.3 and 1 mg/kg doses, whereas NE turnover was decreased in both males and females given 1 mg/kg. Together, these data demonstrate that nicotine primarily affects mediastinal BAT in male rats, consistent with the gender and location of the hibernomas observed in the two-year carcinogenicity study.
Subject(s)
Adipose Tissue, Brown/drug effects , Nicotine/pharmacology , Nicotinic Agonists/pharmacology , Norepinephrine/metabolism , Smoking Cessation , Adipose Tissue, Brown/metabolism , Animals , Benzazepines/toxicity , Dose-Response Relationship, Drug , Female , Lipoma/chemically induced , Lipoma/metabolism , Male , Mediastinal Neoplasms/chemically induced , Mediastinal Neoplasms/metabolism , Nicotine/agonists , Nicotine/toxicity , Nicotinic Agonists/toxicity , Quinoxalines/toxicity , Rats , Rats, Sprague-Dawley , Sex Factors , Smoking Cessation/methods , VareniclineABSTRACT
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide (14, PHA-543,613), a novel agonist of the alpha7 neuronal nicotinic acetylcholine receptor (alpha7 nAChR), has been identified as a potential treatment of cognitive deficits in schizophrenia. Compound 14 is a potent and selective alpha7 nAChR agonist with an excellent in vitro profile. The compound is characterized by rapid brain penetration and high oral bioavailability in rat and demonstrates in vivo efficacy in auditory sensory gating and, in an in vivo model to assess cognitive performance, novel object recognition.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Cognition Disorders/drug therapy , Nicotinic Agonists/chemical synthesis , Nootropic Agents/chemical synthesis , Quinuclidines/chemical synthesis , Receptors, Nicotinic/metabolism , Schizophrenia/drug therapy , Animals , Biological Availability , Brain/metabolism , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Drug Stability , Ether-A-Go-Go Potassium Channels/drug effects , Evoked Potentials, Auditory/drug effects , Humans , In Vitro Techniques , Learning/drug effects , Male , Memory/drug effects , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Neurons/drug effects , Neurons/physiology , Nicotinic Agonists/pharmacokinetics , Nicotinic Agonists/pharmacology , Nootropic Agents/pharmacokinetics , Nootropic Agents/pharmacology , Patch-Clamp Techniques , Quinuclidines/chemistry , Quinuclidines/pharmacology , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptors, Nicotinic/physiology , Recognition, Psychology/drug effects , Stereoisomerism , Structure-Activity Relationship , alpha7 Nicotinic Acetylcholine ReceptorABSTRACT
3,5-Bicyclic aryl piperidines are a new class of high-affinity alpha4beta2 nicotinic receptor agents. We have sought nicotinic receptor partial agonists of the alpha4beta2 nicotinic acetylcholine receptor for smoking cessation, and a number of compounds fulfill potency, selectivity, and efficacy requirements in vitro. In vivo, selected agents demonstrate potent partial agonist efficacy on the mesolimbic dopamine system, a key measure of therapeutic potential for smoking cessation.
Subject(s)
Piperidines/chemistry , Piperidines/pharmacology , Receptors, Nicotinic/metabolism , Smoking Cessation/methods , Animals , Cyclization , Molecular Structure , Piperidines/classification , Rats , Structure-Activity RelationshipABSTRACT
The preparation and biological activity of analogs of (-)-cytisine, an alpha4beta2 nicotinic receptor partial agonist, are discussed. All-carbon-containing phenyl ring replacements of the pyridone ring system, generated via Heck cyclization protocols, exhibited weaker affinity and lower efficacy partial agonist profiles relative to (-)-cytisine. In vivo, selected compounds exhibit lower efficacy partial agonist profiles than that of (-)-cytisine.
Subject(s)
Alkaloids/pharmacology , Carbon/chemistry , Dopamine/metabolism , Nicotinic Agonists/pharmacology , Nucleus Accumbens/drug effects , Receptors, Nicotinic/chemistry , Alkaloids/chemistry , Animals , Azocines/chemistry , Azocines/pharmacology , Nicotinic Agonists/chemistry , Quinolizines/chemistry , Quinolizines/pharmacology , Rats , Receptors, Nicotinic/metabolism , Smoking Cessation , Structure-Activity RelationshipABSTRACT
Herein we describe a novel series of compounds from which varenicline (1, 6,7,8,9-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine) has been identified for smoking cessation. Neuronal nicotinic acetylcholine receptors (nAChRs) mediate the dependence-producing effects of nicotine. We have pursued alpha4beta2 nicotinic receptor partial agonists to inhibit dopaminergic activation produced by smoking while simultaneously providing relief from the craving and withdrawal syndrome that accompanies cessation attempts. Varenicline displays high alpha4beta2 nAChR affinity and the desired in vivo dopaminergic profile.
