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ABSTRACT: Recognition of the importance of the endocannabinoid system in both homeostasis and pathologic responses raised interest recently in the development of therapeutic agents based on this system. The CB(2) receptor, a component of the endocannabinoid system, has significant influence on immune function and inflammatory responses. Inflammatory responses are major contributors to central nervous system (CNS) injury in a variety of diseases. In this report, we present evidence that activation of CB(2) receptors, by selective CB(2) agonists, reduces inflammatory responses that contribute to CNS injury. The studies demonstrate neuroprotective effects in experimental autoimmune encephalomyelitis, a model of multiple sclerosis, and in a murine model of cerebral ischemia/reperfusion injury. In both cases, CB(2) receptor activation results in reduced white cell rolling and adhesion to cerebral microvessels, a reduction in immune cell invasion, and improved neurologic function after insult. In addition, administration of the CB(1) antagonist SR141716A reduces infarct size following ischemia/reperfusion injury. Administration of both a selective CB(2) agonist and a CB(1) antagonist has the unique property of increasing blood flow to the brain during the occlusion period, suggesting an effect on collateral blood flow. In summary, selective CB(2) receptor agonists and CB(1) receptor antagonists have significant potential for neuroprotection in animal models of two devastating diseases that currently lack effective treatment options.
Journal of Neuroimmune Pharmacology 04/2009; 4(2):249-59. · 4.57 Impact Factor
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ABSTRACT: Tobacco use is implicated in approximately 440,000 deaths per year, making it the leading cause of preventable death in the United States. Although it is generally recognized that tobacco use is correlated with a variety of health-related complications, many smokers are unsuccessful in their efforts to stop smoking using current cessation therapies.
Given that nicotine is the addictive component of tobacco, successful smoking cessation therapies must address the various processes, including reward, which contribute to nicotine addiction. As such, determining the nicotinic receptor subtypes involved in nicotine reward is of utmost importance to understanding how nicotine addiction progresses.
Conditioned place preference (CPP) in three-chamber conditioning boxes was performed. For antagonist studies, drug was given on all conditioning sessions 10 min before nicotine or saline injection and placement in the boxes.
We have demonstrated that a pretreatment with the alpha4beta2 subunit of the nicotinic acetylcholine receptor (nAChR) antagonist dihydro-beta-erythroidine (2.0 mg/kg, s.c.) blocked nicotine (0.5 mg/kg, s.c.) CPP in wild-type mice (C57BL/6 mice). In contrast, pretreatment with an antagonist of the alpha7 subunit of the nAChR, methyllycaconitine (MLA, 5.0 or 10.0 mg/kg, s.c.), had no effect on this behavior. Finally, we showed that mice lacking the beta2 subunit of the nAChR did not exhibit nicotine CPP while alpha7 knock-out mice did.
Taken together, these data suggest that the beta2 subunit of the nAChR is critically involved in nicotine reward as measured by CPP.
Psychopharmacologia 04/2006; 184(3-4):339-44. · 4.08 Impact Factor
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Tiziana Bisogno,
Maria Grazia Cascio,
Bijali Saha,
Anu Mahadevan,
Paolo Urbani,
Alberto Minassi,
Giovanni Appendino,
Carmela Saturnino, Billy Martin,
Raj Razdan,
Vincenzo Di Marzo
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ABSTRACT: Enzymes for the biosynthesis and degradation of the endocannabinoid 2-arachidonoyl glycerol (2-AG) have been cloned and are the sn-1-selective-diacylglycerol lipases alpha and beta (DAGLalpha and beta) and the monoacylglycerol lipase (MAGL), respectively. Here, we used membranes from COS cells over-expressing recombinant human DAGLalpha to screen new synthetic substances as DAGLalpha inhibitors, and cytosolic fractions from wild-type COS cells to look for MAGL inhibitors. DAGLalpha and MAGL activities were assessed by using sn-1-[14C]-oleoyl-2-arachidonoyl-glycerol and 2-[3H]-arachidonoylglycerol as substrates, respectively. We screened known compounds as well as new phosphonate derivatives of oleic acid and fluoro-phosphinoyl esters of different length. Apart from the general lipase inhibitor tetrahydrolipstatin (orlistat) (IC50 approximately 60 nM), the most potent inhibitors of DAGLalpha were O-3640 [octadec-9-enoic acid-1-(fluoro-methyl-phosphoryloxymethyl)-propylester] (IC50 = 500 nM), and O-3841 [octadec-9-enoic acid 1-methoxymethyl-2-(fluoro-methyl-phosphinoyloxy)-ethyl ester] (IC50 = 160 nM). Apart from being almost inactive on MAGL, these two compounds showed high selectivity over rat liver triacylglycerol lipase, rat N-acylphosphatidyl-ethanolamine-selective phospholipase D (involved in anandamide biosynthesis), rat fatty acid amide hydrolase and human recombinant cannabinoid CB1 and CB2 receptors. Methylarachidonoyl-fluorophosphonate and the novel compound UP-101 [O-ethyl-O-p-nitro-phenyl oleylphosphonate] inhibited both DAGLalpha and MAGL with similar potencies (IC50 = 0.8-0.1 and 3.7-3.2 microM, respectively). Thus, we report the first potent and specific inhibitors of the biosynthesis of 2-AG that may be used as pharmacological tools to investigate the biological role of this endocannabinoid.
Biochimica et Biophysica Acta 03/2006; 1761(2):205-12. · 4.66 Impact Factor
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ABSTRACT: An examination of several 3-(2-aminoethyl)pyridine analogs suggests that they likely orient at alpha4beta2 nicotinic cholinergic receptors in a different fashion than their correspondingly substituted nicotine analogs.
Bioorganic & Medicinal Chemistry Letters 11/2005; 15(19):4308-12. · 2.55 Impact Factor
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ABSTRACT: 6-(2-Phenylethyl)nicotine (1b; K(i)=15 nM) was unexpectedly found to bind at alpha4beta2 nicotinic cholinergic (nACh) receptors. Although this compound failed to produce nicotine-like agonist action in several functional assays, 1b antagonized the antinociceptive effects of nicotine (mouse tail-flick assay) in a dose-dependent fashion when administered via an intrathecal route.
Bioorganic & Medicinal Chemistry Letters 08/2005; 15(13):3237-40. · 2.55 Impact Factor
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ABSTRACT: As documented in national surveys, for the past several years, marijuana has been the most commonly abused drug in the United States, with approximately 6% of the population 12 years and older having used the drug in the month prior to interview. The use of marijuana is not without significant health hazards. Marijuana is associated with effects on almost every organ system in the body, ranging from the central nervous system to the cardiovascular, endocrine, respiratory/pulmonary, and immune systems. Research presented in this special supplement will show that in addition to marijuana abuse/dependence, marijuana use is associated in some studies with impairment of cognitive function in the young and old, fetal and developmental consequences, cardiovascular effects (heart rate and blood pressure changes), respiratory/pulmonary complications such as chronic cough and emphysema, impaired immune function leading to vulnerability to and increased infections, and the risk of developing head, neck, and/or lung cancer. In general, acute effects are better studied than those of chronic use, and more studies are needed that focus on disentangling effects of marijuana from those of other drugs and adverse environmental conditions.
The Journal of Clinical Pharmacology 12/2002; 42(11 Suppl):7S-10S. · 2.91 Impact Factor
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ABSTRACT: A total of 24 aryl-substituted analogues of nicotine (1a) and two related series of nicotinic ligands, aminomethylpyridines 3 and ether analogues 8, were examined to determine if they bind at alpha4beta2 nACh receptors in a common manner. A modest correlation (r=0.785) was found between the affinities of the nicotine analogues and derivatives of 3, but little correlation (r=0.348) was found with analogues 8. However, a modest correlation (r=0.742) exists between the binding of analogues 3 and 8. It seems that 1-series and 8-series compounds bind differently but that the 3-series compounds share some intermediate binding similarity with both.
Bioorganic & Medicinal Chemistry Letters 09/2002; 12(15):1989-92. · 2.55 Impact Factor
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ABSTRACT: 6,7,8,9-Tetrahydro-5H-pyrido[3,4-d]azepine (5a) and its N7-methyl derivative 5b were synthesized and evaluated as potential nicotinic acetylcholinergic receptor (nAChR) ligands. On the basis that 6,7,8,9-tetrahydro-5H-pyrido[3,4-c]azepine (4a), which binds at nAChRs with low affinity (Ki = 1100 nM), possesses an internitrogen distance (4.6 Å) that may be less than optimal, we designed compound 5a due to its similar shape but longer internitrogen distance (5.5 Å). Compound 5a (Ki = 46 nM) was found to bind with enhanced affinity. However, unlike what is seen with nornicotine/nicotine, N-methylation of 5a reduced affinity (5b; Ki = 268 nM) rather than enhancing it. The results suggest that 5 may interact at nicotine receptors in a manner that is somewhat different from that of nicotine. Ring-opening of the pyrido[3,4-d]azepine ring led to a series of 3-(2-aminoethyl)pyridines 21 that retained the affinity of the cyclic compound. Subsequent modification, including further chain lengthening (e.g. aminopropylpyridines 22) and introduction of unsaturation, ultimately led to the development of a series of 3-(2-aminethoxy)pyridines 27. Simple N-substituted derivatives of 27 were found to bind with Ki values of 20 to 35 nM. Because parallel structural changes in several series of related compounds did not result in parallel shifts in nAChR affinity, it is unlikely that all the investigated compounds bind in a similar fashion at these receptors. Nevertheless, some of these compounds represent novel classes of nAChR ligands.
European Journal of Medicinal Chemistry. 34(2):177-190.
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ABSTRACT: Nicotine 1 binds at nicotinic acetylcholinergic receptors (nAChRs) but relatively little is known regarding its structure–affinity relationships at central receptors. The present study focuses on the pyridine 6-position of nicotine. Earlier studies from our laboratories suggested that the electronic (σ) and/or lipophilic (π) nature of the 6-position substituent might influence nAChR affinity. To examine this in greater detail, we prepared and evaluated a series of 6-substituted nicotine analogs. The various analogs were found to bind at nAChRs with affinities (Ki values) ranging from 0.45 to > 10000 nM. It was demonstrated, for fifteen of these analogs, that affinity could not be explained on the basis of either σ or π. However, a combination of π and Δ MOL VOL (representative of the volume of the 6-position substituent) accounted for affinity (r = 0.970, n = 15). The basicity of the pyridine nitrogen atom was also examined by determining the pKa values of several representative analogs. Consistent with the above studies examining σ, as well as with previously published studies on peripheral nAChR binding, pKa alone did not account for variation in affinity. It would appear that lipophilic substituents at the pyridine 6-position contribute to nAChR affinity of nicotine analogs, but that affinity is further modulated by the steric size of this substituent in that increased size results in decreased affinity.
European Journal of Medicinal Chemistry. 34(1):31-40.
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ABSTRACT: The controlled-substance analog N-monomethyl-1-(4-methoxyphenyl)-2-aminopropane (PMMA) may be viewed as being either the 4-methoxy analog of methamphetamine or the N-methyl analog of 1-(4-methoxyphenyl)-2-aminopropane (PMA). Because of its abuse potential, PMMA was examined with regard to (a) its stimulus properties in rats trained to discriminate either 1.0 mg/kg of (+)amphetamine or (±)DOM from saline, (b) its toxicity (isolated and aggregated) in mice relative to (±)PMA, and (c) its locomotor stimulant activity in mice relative to (±)amphetamine, (±)methamphetamine, and (±)PMA. Racemic PMMA produced neither DOM-like nor, unlike PMA, amphetamine-like stimulus effects. There was no significant difference between the 24-hr isolated (LD50=63 mg/kg) and aggregated (LD50=53 mg/kg) toxicity, and PMMA did not produce significant locomotor stimulation at doses of up to 30 mg/kg. The present results suggest that while PMMA may produce central effects it does not appear to behave as a simple amphetamine-like agent.
Pharmacology Biochemistry and Behavior.
