ABSTRACT
PURPOSE: To examine the effects of incorporating tribal specific cultural beliefs into a tailored substance abuse prevention intervention for at risk rural Oklahoma Native American Indian (NAI) Plains adolescents. RESEARCH DESIGN: The 10 hour Native American Talking Circle Intervention, a school-based, group substance abuse prevention program, was implemented over a 8.5 week period and evaluated using a one group, pretest-posttest design. Measurements were from the Native Self-Reliance Questionnaire and the Substance Problems Scale from Global Appraisal of Individual Needs-Quick (GAIN-Q). FINDINGS: One-tailed, paired sample t-tests demonstrated significant increase in self-reliance, from 86.227 to 92.204 (t (43) = -2.580, p = .007) and a decrease in substance abuse/use, from 2.265 to 1.265 (t (33) = 1.844, p = .007). CONCLUSIONS: The Native Talking Circle Intervention based on tribal-specific values and beliefs was shown to be effective with substance abuse/use at-risk NAI Plains tribal adolescents.
Subject(s)
Adolescent Behavior/ethnology , Cultural Characteristics , Health Promotion/methods , Indians, North American/ethnology , School Health Services/organization & administration , Substance-Related Disorders/ethnology , Substance-Related Disorders/prevention & control , Adolescent , Female , Humans , Male , Oklahoma/ethnologyABSTRACT
Facilitating activation, or delaying inactivation, of the native Kv7 channel reduces neuronal excitability, which may be beneficial in controlling spontaneous electrical activity during epileptic seizures. In an effort to identify a compound with such properties, the structure-activity relationship (SAR) and in vitro ADME for a series of heterocyclic Kv7.2-7.5 channel openers was explored. PF-05020182 (2) demonstrated suitable properties for further testing in vivo where it dose-dependently decreased the number of animals exhibiting full tonic extension convulsions in response to corneal stimulation in the maximal electroshock (MES) assay. In addition, PF-05020182 (2) significantly inhibited convulsions in the MES assay at doses tested, consistent with in vitro activity measure. The physiochemical properties, in vitro and in vivo activities of PF-05020182 (2) support further development as an adjunctive treatment of refractory epilepsy.
Subject(s)
Drug Discovery , Epilepsy/drug therapy , Ion Channel Gating/drug effects , KCNQ2 Potassium Channel/metabolism , Piperidines/pharmacology , Pyrimidines/pharmacology , Animals , Cell Line , Dose-Response Relationship, Drug , Electroshock , Humans , KCNQ2 Potassium Channel/agonists , Microsomes/drug effects , Molecular Structure , Piperidines/administration & dosage , Piperidines/chemistry , Pyrimidines/administration & dosage , Pyrimidines/chemistry , Rats , Structure-Activity RelationshipABSTRACT
The decline in productivity of the pharmaceutical industry may stem, at least in part, from underestimating the complexity of human disease. While a disease-relevant gene or protein may initially seem to be an attractive drug target, appreciating its role in the network of pathways involved in a disease provides a better perspective for making this decision. In some cases, off-target effects or redundancy in the network can negate the potential efficacy of a new drug. Even a successful drug, such as imatinib (Gleevec), may be less selective than originally thought, resulting in important, and sometimes useful, consequences. Advances in the area of network biology provide an important perspective on the potential of a drug target, and are being applied to various diseases. The impact of these advances on the field of drug discovery is assessed.
Subject(s)
Drug Discovery/methods , Drug Industry/trends , Metabolic Networks and Pathways , Systems Biology , Animals , Drug Discovery/trends , Humans , Pharmaceutical Preparations/metabolismABSTRACT
We report the synthesis of a series of [3.2.1]azabicyclic biaryl ethers as selective agonists of alpha3- and alpha6-containing nicotinic receptors. In particular, compound 17a from this series is a potent alpha3beta4 and alpha6/4beta4 receptor agonist in terms of both binding and functional activity. Compound 17a also shows potent in vivo activity in CNS-mediated animal models that are sensitive to antipsychotic drugs. Compound 17a may thus be a useful tool for studying the role of alpha3beta4 and alpha6/4beta4 nicotinic receptors in CNS pharmacology.
Subject(s)
Azabicyclo Compounds/chemistry , Nicotinic Agonists/chemistry , Receptors, Nicotinic/chemistry , Sulfonamides/chemistry , Azabicyclo Compounds/chemical synthesis , Azabicyclo Compounds/pharmacology , Nicotinic Agonists/chemical synthesis , Nicotinic Agonists/pharmacology , Receptors, Nicotinic/metabolism , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacologyABSTRACT
We describe a novel series of inhibitors of the type 1 glycine transporter (GlyT1) as an approach to relieving the glutamatergic deficit that is thought to underlie schizophrenia. Synthesis and SAR follow-up of a series of octahydro-cyclopenta[c]pyrrole derivatives afforded potent in vitro inhibition of GlyT1 as well as in vivo activity in elevating CSF glycine. We also found that a 3-O(c-pentyl), 4-F substituent may serve as a surrogate for the widely used 3-trifluoromethoxy group, suggesting its application as an isostere for future medicinal chemistry studies.
Subject(s)
Cyclopentanes/chemistry , Glycine Plasma Membrane Transport Proteins/antagonists & inhibitors , Pyrroles/chemistry , Animals , Cell Line , Cyclopentanes/pharmacology , Dogs , Glycine Plasma Membrane Transport Proteins/physiology , Humans , Microsomes/drug effects , Microsomes/physiology , Pyrroles/pharmacologySubject(s)
Anti-Bacterial Agents/pharmacology , Anti-Obesity Agents/pharmacology , Antineoplastic Agents/pharmacology , Central Nervous System Agents/pharmacology , Drug Discovery , Validation Studies as Topic , Animals , Anti-Bacterial Agents/adverse effects , Anti-Obesity Agents/adverse effects , Antineoplastic Agents/adverse effects , Central Nervous System Agents/adverse effects , Disease Models, Animal , Drug Design , Drug Evaluation, Preclinical , Humans , RNA Interference , Species Specificity , Treatment FailureABSTRACT
The type 1 glycine transporter plays an important in regulating homeostatic glycine levels in the brain that are relevant to the activation of the NMDA receptor by the excitatory neurotransmitter glutamate. We describe herein the structure-activity relationships (SAR) of a structurally novel class of GlyT1 inhibitors following on a lead derived from high throughput screening, which shows good selectivity for GlyT1 and potent activity in elevating CSF levels of glycine.
Subject(s)
Aza Compounds/chemistry , Glycine Plasma Membrane Transport Proteins/antagonists & inhibitors , Heterocyclic Compounds, 2-Ring/chemistry , Aza Compounds/chemical synthesis , Aza Compounds/pharmacology , Cell Line , Drug Design , Glycine/metabolism , Glycine Plasma Membrane Transport Proteins/metabolism , Heterocyclic Compounds, 2-Ring/chemical synthesis , Heterocyclic Compounds, 2-Ring/pharmacology , Humans , Receptors, N-Methyl-D-Aspartate/metabolism , Structure-Activity RelationshipABSTRACT
The role of the medicinal chemist in drug discovery has undergone major changes in the past 25 years, mainly because of the introduction of technologies such as combinatorial chemistry and structure-based drug design. As medicinal chemists with more than 50 years of combined experience spanning the past four decades, we discuss this changing role using examples from our own and others' experience. This historical perspective could provide insights in to how to improve the current model for drug discovery by helping the medicinal chemist regain the creative role that contributed to past successes.
Subject(s)
Chemistry, Pharmaceutical/history , Drug Design , Medical Laboratory Personnel/history , Medical Laboratory Personnel/trends , Pharmaceutical Preparations/chemical synthesis , Pharmaceutical Preparations/history , Chemistry, Pharmaceutical/methods , Chemistry, Pharmaceutical/trends , Europe , History, 20th Century , History, 21st Century , Humans , United StatesABSTRACT
The synthesis and nNOS and eNOS activity of 6-(4-(dimethylaminoalkyl)-/6-(4-(dimethylaminoalkoxy)-5-ethyl-2-methoxyphenyl)-pyridin-2-ylamines and 6-(4-(dimethylaminoalkyl)-/6-(4-(dimethylaminoalkoxy)-2,5-dimethoxyphenyl)-pyridin-2-ylamines 1-8 are described. These compounds are potent inhibitors of the human nNOS isoform.
Subject(s)
Amines/chemistry , Enzyme Inhibitors/chemistry , Nerve Tissue Proteins/antagonists & inhibitors , Nitric Oxide Synthase/antagonists & inhibitors , Pyridines/chemistry , Amines/pharmacology , Enzyme Inhibitors/pharmacology , Humans , Neural Inhibition/drug effects , Nitric Oxide Synthase Type I , Pyridines/pharmacologyABSTRACT
Long-term potentiation (LTP) in the hippocampal CA1 region requires the activation of NMDA receptors (NMDARs). NMDAR activation in turn requires membrane depolarization as well as the binding of glutamate and its coagonist glycine. Previous pharmacological studies suggest that the glycine transporter type 1 (GlyT1) maintains subsaturating concentrations of glycine at synaptic NMDARs. Antagonists of GlyT1 increase levels of glycine in the synaptic cleft and, like direct glycine site agonists, can augment NMDAR currents and NMDAR-mediated functions such as LTP. In addition, stimulation of the glycine site initiates signalling through the NMDAR complex, priming the receptors for clathrin-dependent endocytosis. We have used a new potent GlyT1 antagonist, CP-802,079, with whole-cell patch-clamp recordings in acute rat hippocampal slices to determine the effect of GlyT1 blockade on LTP. Reverse microdialysis experiments in the hippocampus of awake, freely moving rats, showed that this drug elevated only the extracellular concentration of glycine. We found that CP-802,079, sarcosine and glycine significantly increased the amplitude of the NMDAR currents and LTP. In contrast, application of higher concentrations of CP-802,079 and glycine slightly reduced NMDAR currents and did not increase LTP. Overall, these data suggest that the level of glycine present in the synaptic cleft tightly regulates the NMDAR activity. This level is kept below the 'set point' of the NMDAR internalization priming mechanism by the presence of GlyT1-dependent uptake.
Subject(s)
Acetates/pharmacology , Amino Acid Transport Systems, Neutral/antagonists & inhibitors , Glycine/metabolism , Long-Term Potentiation/drug effects , Pyramidal Cells/drug effects , Receptors, N-Methyl-D-Aspartate/drug effects , Thiazoles/pharmacology , Animals , Glycine/pharmacology , Glycine Plasma Membrane Transport Proteins , Hippocampus/cytology , Hippocampus/drug effects , In Vitro Techniques , Male , Patch-Clamp Techniques , Pyramidal Cells/physiology , Rats , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/agonists , Receptors, N-Methyl-D-Aspartate/metabolism , Sarcosine/pharmacologyABSTRACT
The synthesis and structure-activity relationships of a series of 6-phenyl-2-aminopyridines that potently and selectively inhibit the neuronal isoform of nitric oxide synthase (nNOS) are described. Compound 14bi from this series exhibits potent in vivo activity in harmaline-induced cGMP formation in rat cerebellum, a functional model of nNOS inhibition, and in the PCP-induced hypermotility model in the rat. These results suggest that 14bi may be a useful reagent for evaluating potential therapeutic applications of nNOS inhibitors in the central nervous system.
Subject(s)
Aminopyridines/chemical synthesis , Nitric Oxide Synthase/antagonists & inhibitors , Tetrahydronaphthalenes/chemical synthesis , Aminopyridines/chemistry , Aminopyridines/pharmacology , Animals , Cerebellum/drug effects , Cerebellum/metabolism , Cyclic GMP/biosynthesis , Male , Motor Activity/drug effects , Nitric Oxide Synthase/chemistry , Nitric Oxide Synthase Type I , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Tetrahydronaphthalenes/chemistry , Tetrahydronaphthalenes/pharmacologyABSTRACT
The synthesis of NPTS, 6, a potent inhibitor of the type 1 glycine transporter (GlyT1) is described, as well as preparation of 6 in optically active and tritiated form for use as a radioligand for affinity displacement assay of GlyT1.
