Potency of Michael reaction acceptors as inducers of enzymes that protect against carcinogenesis depends on their reactivity with sulfhydryl groups

Induction of phase 2 enzymes and elevations of glutathione are major and sufficient strategies for protecting mammals and their cells against the toxic and carcinogenic effects of electrophiles and reactive forms of oxygen. Inducers belong to nine chemical classes and have few common properties except for their ability to modify sulfhydryl groups by oxidation, reduction, or alkylation. Much evidence suggests that the cellular “sensor” molecule that recognizes the inducers and signals the enhanced transcription of phase 2 genes does so by virtue of unique and highly reactive sulfhydryl functions that recognize and covalently react with the inducers. Benzylidene-alkanones and -cycloalkanones are Michael reaction acceptors whose inducer potency is profoundly increased by the presence of ortho- (but not other) hydroxyl substituent(s) on the aromatic ring(s). This enhancement correlates with more rapid reactivity of the ortho-hydroxylated derivatives with model sulfhydryl compounds. Proton NMR spectroscopy provides no evidence for increased electrophilicity of the β-vinyl carbons (the presumed site of nucleophilic attack) on the hydroxylated inducers. Surprisingly, these ortho-hydroxyl groups display a propensity for extensive intermolecular hydrogen bond formation, which may raise the reactivity and facilitate addition of mercaptans, thereby raising inducer potencies.

Structural basis for specificity and potency of a flavonoid inhibitor of human CDK2, a cell cycle kinase.

The central role of cyclin-dependent kinases (CDKs) in cell cycle regulation makes them a promising target for studying inhibitory molecules that can modify the degree of cell proliferation. The discovery of specific inhibitors of CDKs such as polyhydroxylated flavones has opened the way to investigation and design of antimitotic compounds. A novel flavone, (-)-cis-5,7-dihydroxyphenyl-8-[4-(3-hydroxy-1-methyl)piperidinyl] -4H-1-benzopyran-4-one hydrochloride hemihydrate (L868276), is a potent inhibitor of CDKs. A chlorinated form, flavopiridol, is currently in phase I clinical trials as a drug against breast tumors. We determined the crystal structure of a complex between CDK2 and L868276 at 2.33 angstroms resolution and refined to an Rfactor 20.3%. The aromatic portion of the inhibitor binds to the adenine-binding pocket of CDK2, and the position of the phenyl group of the inhibitor enables the inhibitor to make contacts with the enzyme not observed in the ATP complex structure. The analysis of the position of this phenyl ring not only explains the great differences of kinase inhibition among the flavonoid inhibitors but also explains the specificity of L868276 to inhibit CDK2 and CDC2.

Ultra-low concentrations of naloxone selectively antagonize excitatory effects of morphine on sensory neurons, thereby increasing its antinociceptive potency and attenuating tolerance/dependence during chronic cotreatment.

Ultra-low picomolar concentrations of the opioid antagonists naloxone (NLX) and naltrexone (NTX) have remarkably potent antagonist actions on excitatory opioid receptor functions in mouse dorsal root ganglion (DRG) neurons, whereas higher nanomolar concentrations antagonize excitatory and inhibitory opioid functions. Pretreatment of naive nociceptive types of DRG neurons with picomolar concentrations of either antagonist blocks excitatory prolongation of the Ca(2+)-dependent component of the action potential duration (APD) elicited by picomolar-nanomolar morphine and unmasks inhibitory APD shortening. The present study provides a cellular mechanism to account for previous reports that low doses of NLX and NTX paradoxically enhance, instead of attenuate, the analgesic effects of morphine and other opioid agonists. Furthermore, chronic cotreatment of DRG neurons with micromolar morphine plus picomolar NLX or NTX prevents the development of (i) tolerance to the inhibitory APD-shortening effects of high concentrations of morphine and (ii) supersensitivity to the excitatory APD-prolonging effects of nanomolar NLX as well as of ultra-low (femtomolar-picomolar) concentrations of morphine and other opioid agonists. These in vitro studies suggested that ultra-low doses of NLX or NTX that selectively block the excitatory effects of morphine may not only enhance the analgesic potency of morphine and other bimodally acting opioid agonists but also markedly attenuate their dependence liability. Subsequent correlative studies have now demonstrated that cotreatment of mice with morphine plus ultra-low-dose NTX does, in fact, enhance the antinociceptive potency of morphine in tail-flick assays and attenuate development of withdrawal symptoms in chronic, as well as acute, physical dependence assays.

LEM1, an ATP-binding-cassette transporter, selectively modulates the biological potency of steroid hormones.

The rat glucocorticoid receptor confers hormone-dependent transcriptional enhancement when expressed in yeast, thereby enabling the genetic identification of nonreceptor proteins that function in the hormone signal-transduction pathway. We isolated a yeast mutant, lem1, with increased sensitivity to dexamethasone and triamcinolone acetonide; responsiveness to a third agonist, deoxycorticosterone, is unaffected. Cloning of wild-type LEM1 revealed a putative transport protein of the ATP-binding cassette family. Dexamethasone accumulation is increased in lem1 cells, suggesting that wild-type LEM1 decreases dexamethasone potency by exporting this ligand. LEM1 appears to affect certain steroids and not others. We propose that transporters like LEM1 can selectively modulate the intracellular levels of steroid hormones. Differential activities of such transporters in mammalian cells might regulate hormone availability and thereby hormone signaling in a cell-type specific manner.

Public Lawyers and Marijuana Regulation

Although 23 states and the District of Columbia have now legalized marijuana for medical purposes, marijuana remains a prohibited substance under federal law. Because the production, sale, possession and use of marijuana remain illegal, there is a risk of prosecution under federal laws. Furthermore, those who help marijuana users and providers put themselves at risk — federal law punishes not only those who violate drug laws but also those who assist or conspire with them to do so. In the case of lawyers representing marijuana users and businesspeople, this means not only the real (though remote) risk of criminal prosecution but also the more immediate risk of professional discipline. Elsewhere, we wrote about the difficult place in which lawyers find themselves when representing marijuana clients. We argued that while both the criminal law and the rules of professional conduct rightly require legal obedience from lawyers, other countervailing factors must be considered when evaluating lawyers’ representation of marijuana clients. In particular, we asserted that considerations of equity and access to justice weigh dispositively in favor of protecting lawyers who endeavor to help their clients comply with state marijuana laws, and we suggested means of interpreting relevant criminal law provisions and rules of professional conduct to achieve this result. This article builds on that analysis, taking on the particular issue of the public lawyer’s’ role in marijuana regulation. For government lawyers, the key issues in exercising discretion in the context of marijuana are not clients’ access to the law and equality but rather determining the clients’ wishes and serving them diligently and ethically. Lawyers representing state agencies, legislatures and the executive branch of government draft and interpret the rules and regulations regarding marijuana. Lawyers for federal, state and local governments then interpret those rules to determine the obligations and responsibilities of those they represent and to help their clients meet those obligations and carry out their required tasks. Both state and federal prosecutors are charged with determining what conduct remains illegal under the new rules and, perhaps more importantly, with exercising discretion regarding whom to prosecute and to what extent. Marijuana regulation is not a niche area of government regulation; it will influence the practice of virtually every public lawyer in the years to come. Public lawyers must understand the changes in marijuana law and the implications for government clients. Given the pervasiveness of the modern regulatory state, the situation is no easier — and, in many ways, it is more complicated — for public lawyers than it is for private ones. Public lawyers face myriad practice challenges with respect to marijuana law reform, and while we do not purport to identify and resolve all of the issues that are sure to arise in this short paper, we hope that the article helps alert public lawyers to some of the risks involved in participating in marijuana regulation so that they can think carefully about their obligations when these issues arise.

Marijuana Legalization in Colorado -- Lessons for Colombia

In 2012 Colorado became the first jurisdiction anywhere in the world to legalize marijuana possession and use for all adults. The regulated and taxed marijuana industry that arose in Colorado following legalization was also the first of its kind and stands a model for other states considering marijuana law reform. In this brief article I discuss the results of the Colorado experiment; I demonstrate that while Colorado’s regulatory model was largely successful, it also demonstrates the limits of generating revenue through taxing and regulating marijuana. I then discuss the implications of this conclusion for post-conflict Colombia, drawing a comparison to the situation California confronts as it considers legalizing marijuana for adult use.

The Battle of the Bulge: The Surprising Last Stand Against State Marijuana Legalization

Although marijuana possession remains a federal crime, twenty-three states now allow use of marijuana for medical purposes and four states have adopted tax-and-regulate policies permitting use and possession by those twenty-one and over. In this article, I examine recent developments regarding marijuana regulation. I show that the Obama administration, after initially sending mixed signals, has taken several steps indicating an increasingly accepting position toward marijuana law reform in states; however the current situation regarding the dual legal status of marijuana is at best an unstable equilibrium. I also focus on what might be deemed the last stand of marijuana-legalization opponents, in the form of lawsuits filed by several states, sheriffs, and private plaintiffs challenging marijuana reform in Colorado (and by extension elsewhere). This analysis offers insights for federalism scholars regarding the speed with which marijuana law reform has occurred, the positions taken by various state and federal actors, and possible collaborative federalism solutions to the current state-federal standoff.

The Limits of Marijuana Legalization in the States

Although some ingenious solutions have been proposed to the problems posed by Section 280E pf the federal tax code, the situation remains untenable. The only solution to this current conundrum is a change in federal law; so long as marijuana remains illegal under the Controlled Substances Act, state marijuana policy will inevitably be frustrated. This brief response to an article by Professor Leff identifies some of these frustrations and proposes a few modest federal solutions

Representing Clients in the Marijuana Industry: Navigating State and Federal Rules

As the number of states legalizing medicinal and recreational marijuana increases and marijuana emerges as a growing lawful industry, lawyers find themselves in an awkward position. In most states, lawyers who represent clients in the marijuana industry risk discipline for assisting clients in the commission of a (federal) crime. Even in jurisdictions like Colorado, where the rules of professional conduct have been amended to permit lawyers to assist clients who comply with marijuana state laws, lawyers who are admitted to practice in federal courts risk being disciplined by these tribunals for assisting clients in the commission of a crime pursuant to the courts’ local rules of conduct. This short article explores the thorny issue of navigating state and federal rules of professional conduct while representing clients in the marijuana industry.

U.S.-Mexico opium poppy and marijuana aerial eradication program /

At head of title: United States General Accounting Office. Testimony.

The role of alcohol, marijuana and other drugs in the accidents of injured drivers. [Revised edition].

National Highway Traffic Safety Administration, Washington, D.C.

Marijuana, alcohol and actual driving performance.

National Highway Traffic Safety Administration, Washington, D.C.

Marijuana, other drugs and their relation to highway safety: a report to the Congress.

Mode of access: Internet.

Marijuana : a study of state policies & penalties /

Mode of access: Internet.