ABSTRACT
Observations that N-Methyl-D-Aspartate (NMDA) antagonists produce symptoms in humans that are similar to those seen in schizophrenia have led to the current hypothesis that schizophrenia might result from NMDA receptor hypofunction. Inhibition of D-amino acid oxidase (DAAO), the enzyme responsible for degradation of D-serine, should lead to increased levels of this co-agonist at the NMDA receptor, and thereby provide a therapeutic approach to schizophrenia. We have profiled some of the preclinical biochemical, electrophysiological, and behavioral consequences of administering potent and selective inhibitors of DAAO to rodents to begin to test this hypothesis. Inhibition of DAAO activity resulted in a significant dose and time dependent increase in D-serine only in the cerebellum, although a time delay was observed between peak plasma or brain drug concentration and cerebellum D-serine response. Pharmacokinetic/pharmacodynamic (PK/PD) modeling employing a mechanism-based indirect response model was used to characterize the correlation between free brain drug concentration and D-serine accumulation. DAAO inhibitors had little or no activity in rodent models considered predictive for antipsychotic activity. The inhibitors did, however, affect cortical activity in the Mescaline-Induced Scratching model, produced a modest but significant increase in NMDA receptor-mediated synaptic currents in primary neuronal cultures from rat hippocampus, and resulted in a significant increase in evoked hippocampal theta rhythm, an in vivo electrophysiological model of hippocampal activity. These findings demonstrate that although DAAO inhibition did not cause a measurable increase in D-serine in forebrain, it did affect hippocampal and cortical activity, possibly through augmentation of NMDA receptor-mediated currents.
Subject(s)
Brain/metabolism , D-Amino-Acid Oxidase/antagonists & inhibitors , Memory, Short-Term/physiology , Psychomotor Agitation/drug therapy , Receptors, N-Methyl-D-Aspartate/metabolism , Animals , Brain/drug effects , Central Nervous System Stimulants/metabolism , Central Nervous System Stimulants/pharmacology , Cyclic GMP/analysis , Cyclic GMP/biosynthesis , D-Amino-Acid Oxidase/metabolism , D-Amino-Acid Oxidase/physiology , Drug Evaluation, Preclinical , Electroencephalography , Habituation, Psychophysiologic/drug effects , Habituation, Psychophysiologic/physiology , Harmaline/metabolism , Hippocampus/drug effects , Hippocampus/metabolism , Male , Maze Learning/drug effects , Maze Learning/physiology , Memory, Short-Term/drug effects , Mescaline/pharmacology , Mice , Miniature Postsynaptic Potentials/drug effects , Miniature Postsynaptic Potentials/physiology , Models, Biological , Models, Chemical , Molecular Targeted Therapy , Motor Activity/drug effects , Motor Activity/physiology , Pruritus/chemically induced , Pruritus/prevention & control , Rats , Rats, Long-Evans , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/drug effects , Sensory Gating/drug effects , Sensory Gating/physiology , Serine/blood , Serotonin Receptor Agonists/pharmacologyABSTRACT
PDE10A is a member of the phosphodiesterase superfamily highly enriched within medium spiny neurons (MSN) in mammalian striatum. We have used inhibitors of PDE10A and quantitative measures of mRNA to demonstrate that PDE10A controls striatal gene expression by regulating MSN cyclic nucleotide signaling pathways. Acute treatment with PDE10A inhibitors produces rapid and transient transcription of the immediate early gene cfos in rat striatum. Although inhibition of PDE10A causes accumulation of both cAMP and cGMP, the increase in striatal cfos expression appears to depend on changes in cAMP, since the increase is present in mice deficient in nNOS which fail to increase cGMP in response to PDE10A inhibition. Consistent with its expression in a majority of striatal MSN, PDE10A inhibition significantly induces expression of both substance P and enkephalin, neuropeptide markers for the direct and indirect striatal output pathways, respectively. These findings support the hypothesis that PDE10A modulates signal transduction in both striatal output pathways and suggest that PDE10A inhibitors may offer a unique approach to the treatment of schizophrenia.
Subject(s)
Corpus Striatum/drug effects , Corpus Striatum/metabolism , Gene Expression Regulation/drug effects , Phosphoric Diester Hydrolases/metabolism , Proto-Oncogene Proteins c-fos/genetics , Animals , Cyclic AMP/genetics , Cyclic AMP/metabolism , Cyclic GMP/genetics , Cyclic GMP/metabolism , Enkephalins/genetics , Enkephalins/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Inbred Strains , Mice, Knockout , Neurons/drug effects , Neurons/metabolism , Nitric Oxide Synthase Type I/genetics , Papaverine/pharmacology , Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester Hydrolases/genetics , Proto-Oncogene Proteins c-fos/metabolism , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Substance P/genetics , Substance P/metabolismABSTRACT
A rising concern among clinicians is treatment of unplanned weight loss in the elderly, especially given the predicted growth of this population over the next few decades. Unexpected weight loss in the geriatric patient worsens overall health outcomes. A variety of pharmacotherapeutic options are available for treatment; however, evidence underlying their use is limited, and none has gained approval from the United States Food and Drug Administration for this indication. At present, no guidelines support the choice of one agent over another. Although several drug interventions have been employed for this problem, megestrol acetate and mirtazapine are becoming increasingly used for appetite stimulation. These drugs represent two feasible options for geriatric patients because of their generally favorable adverse-effect profiles and few drug interactions, but they are often misused. In a comprehensive search of the MEDLINE and International Pharmaceutical Abstracts databases, we identified all published reports on the use of megestrol acetate or mirtazapine for the treatment of weight loss and on any adverse events associated with these drugs. Special emphasis was placed on trials performed in an elderly population. Results were conflicting, most likely because of differing study designs and small numbers of patients. Megestrol acetate and mirtazapine appear to be effective for appetite stimulation and weight gain in some settings. However, applicability of the data to elderly individuals is unclear, and adverse events reported in a few of the trials and in case reports were not benign. Therefore, the use of megestrol acetate or mirtazapine for weight loss should be thoroughly evaluated on an individual basis. Pharmacotherapy should be used only after all underlying causes of weight loss are assessed and treated.
Subject(s)
Antidepressive Agents, Tricyclic/therapeutic use , Appetite Stimulants/therapeutic use , Megestrol Acetate/therapeutic use , Mianserin/analogs & derivatives , Weight Loss/drug effects , Aged , Antidepressive Agents, Tricyclic/adverse effects , Appetite Stimulants/adverse effects , Cachexia/physiopathology , Case-Control Studies , Dose-Response Relationship, Drug , Drug Monitoring , Humans , Megestrol Acetate/adverse effects , Mianserin/adverse effects , Mianserin/therapeutic use , Mirtazapine , Prospective Studies , Randomized Controlled Trials as Topic , Retrospective Studies , Time Factors , Wasting Syndrome/physiopathology , Weight Loss/physiologyABSTRACT
A novel fused tricyclic analog (11) of cytisine has been prepared (coined 'cyfusine') and determined to have high affinity at neuronal nicotinic acetylcholine receptors. A [3+2] cycloaddition protocol permitted entry into a 3,4-differentially difunctionalized dihydropyrrole (7). The penultimate cyclization was accomplished using the modified Van Tamelen conditions developed in our earlier synthesis of (+/-)-cytisine. Sequential ring-forming reactions ([3+2] cycloaddition/cyclopropanation/pyridone cyclization) gives a unique cyclopropyl analog (16) possessing a skeleton isoatomic with that of cytisine.
Subject(s)
Alkaloids/chemistry , Heterocyclic Compounds, 3-Ring/chemistry , Pyridones/chemical synthesis , Pyrroles/chemical synthesis , Receptors, Nicotinic/chemistry , Azocines/chemistry , Cyclization , Cyclopropanes/chemistry , Models, Chemical , Pyridones/chemistry , Pyridones/metabolism , Pyrroles/chemistry , Pyrroles/metabolism , Quinolizines/chemistry , Receptors, Nicotinic/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A papaverine based pharmacophore model for PDE10A inhibition was generated via SBDD and used to design a library of 4-amino-6,7-dimethoxyquinazolines. From this library emerged an aryl ether pyrrolidyl 6,7-dimethoxyquinazoline series that became the focal point for additional modeling, X-ray, and synthetic efforts toward increasing PDE10A inhibitory potency and selectivity versus PDE3A/B. These efforts culminated in the discovery of 29, a potent and selective brain penetrable inhibitor of PDE10A.
Subject(s)
Phosphodiesterase Inhibitors/chemical synthesis , Phosphoric Diester Hydrolases/metabolism , Pyrrolidines/chemical synthesis , Quinazolines/chemical synthesis , Animals , Corpus Striatum/metabolism , Crystallography, X-Ray , Cyclic GMP/metabolism , Mice , Models, Molecular , Phosphodiesterase Inhibitors/chemistry , Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester Hydrolases/chemistry , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Quinazolines/chemistry , Quinazolines/pharmacology , Structure-Activity RelationshipABSTRACT
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.
