Jeffrey A. Stafford

A highly selective protocol for the deprotection of BOC-protected amides and carbamates

Abstract A BOC-protected amide or carbamate undergoes mild and selective deprotection by treatment with catalytic Mg(ClO 4 ) 2 in acetonitrile. Simple BOC-protected amines are not affected by these conditions.

CNS 7056: a novel ultra-short-acting Benzodiazepine.

Background:A new benzodiazepine derivative, CNS 7056, has been developed to permit a superior sedative profile to current agents, i.e., more predictable fast onset, short duration of sedative action, and rapid recovery profile. This goal has been achieved by rendering the compound susceptible to metabolism via esterases. The authors now report on the profile of CNS 7056 in vitro and in vivo. Methods:The affinity of CNS 7056 and its carboxylic acid metabolite, CNS 7054, for benzodiazepine receptors and their selectivity profiles were evaluated using radioligand binding. The activity of CNS 7056 and midazolam at subtypes (α1β2γ2, α2β2γ2, α3β2γ2, α5β2γ2) of the γ-aminobutyric acid type A (GABAA) receptor was evaluated using the whole cell patch clamp technique. The activity of CNS 7056 at brain benzodiazepine receptors in vivo was measured in rats using extracellular electrophysiology in the substantia nigra pars reticulata. The sedative profile was measured in rodents using the loss of righting reflex test. Results:CNS 7056 bound to brain benzodiazepine sites with high affinity. The carboxylic acid metabolite, CNS 7054, showed around 300 times lower affinity. CNS 7056 and CNS 7054 (10 μm) showed no affinity for a range of other receptors. CNS 7056 enhanced GABA currents in cells stably transfected with subtypes of the GABAA receptor. CNS 7056, like midazolam and other classic benzodiazepines, did not show clear selectivity between subtypes of the GABAA receptor. CNS 7056 (intravenous) caused a dose-dependent inhibition of substantia nigra pars reticulata neuronal firing and recovery to baseline firing rates was reached rapidly. CNS 7056 (intravenous) induced loss of the righting reflex in rodents. The duration of loss of righting reflex was short (< 10 min) and was inhibited by pretreatment with flumazenil. Conclusions:CNS 7065 is a high-affinity and selective ligand for the benzodiazepine site on the GABAA receptor. CNS 7056 does not show selectivity between GABAA receptor subtypes. CNS 7056 is a potent sedative in rodents with a short duration of action. Inhibition of substantia nigra pars reticulata firing and the inhibition of the effects of CNS 7056 by flumazenil show that it acts at the brain benzodiazepine receptor.

Short-acting benzodiazepines

council. Education and training are currently among the most important issues in the personal social services. Community care requires social workers to extend their range by adding budgetary, managerial, and coordinating responsibilities to their traditional tasks of assessment and casework. Training must also cover the knowledge and skills required for working with both children and adults and provide the ethical and legal grounding that social work needs. Two years of full time education is too short a time to establish competence across the whole range of a social workers statutory duties; the issue is not whether a third year is desirable but whether it should be spent before or after qualification. Social workers often operate in circumstances where moral values are confused and in conflict and where no single outcome is likely to satisfy all those concerned. Compulsory admission, child care, child protection, fostering and adoption, assessing risk in community and residential careall these are matters on which social workers encounter divided views on values, principles, and policy. Social work must therefore have a secure ethical basis for its professional and educational structures. Practitioners confronted by moral dilemmas and insoluble problems also need the guidance and support of a comprehensive professional organisation. Its advice and findings then form part of the bedrock of professional education. The absence of such a professional structure hampers the incorporation of ethical and technical elements into education. The proposed general council would fill this gap effectively and economically. Social works close association with local government has brought it both costs and benefits. Social workers, in a role that requires professional self-direction, are asked to function as part of the welfare bureaucracy and as front line troops performing statutory duties. But local government also provides social workers with a crucial role in protecting vulnerable people and in securing valuable services for them. It will remain a rewarding setting for the practice of social work, and social workers will continue to make an important contribution to the welfare of the community from a base in local government. The necessary condition is that they receive responsible political leadership, effective management, and proper resources. The narrow focus of statutory services now prevents social work from directly addressing the consequences of unemployment, poverty, and homelessness. A new statutory framework is required for services to adults that redirects the energies of social work to these needs and fulfils all the aspirations of community care policies. Social work should also seek to develop as a professional activity in voluntary and private agencies and in the NHS. The requirement for local authorities to meet the health services need for social work has broken down in significant areas. Health services should once again be able to employ social workers, and social work should be one of the services offered by NHS hospitals and trusts, community health services, and general practices. BILL UTTING Chairman

An efficient and mild synthesis of highly substituted imidazoles

Abstract A versatile, one-step imidazole synthesis employing vicinal tricarbonyl compounds is described.

Identification and structure-activity studies of novel ultrashort-acting benzodiazepine receptor agonists

The synthesis and evaluation of novel ultrashort-acting benzodiazepine (USA BZD) agonists is described. A BZD scaffold was modified by incorporation of amino acids and derivatives. The propionate side chain of glutamic acid tethers an enzymatically labile functionality where the metabolite carboxylic acid displays markedly reduced BZD receptor affinity. The USA BZDs were characterized by full agonism profiles. Copyright2000 Elsevier Science Ltd.

Relating the structure, activity, and physical properties of ultrashort-acting benzodiazepine receptor agonists.

The ultrashort-acting benzodiazepine (USA BZD) agonists reported previously have been structurally modified to improve aqueous solubility. Lactam-to-amidine modifications, replacement of the C5-haloaryl ring, and annulation of heterocycles are presented. These analogues retain BZD receptor potency and full agonism profiles.

Structure-activity relationships involving the catechol subunit of rolipram

Abstract Structure-activity relationships involving the aromatic ring of the selective PDE IV inhibitor, rolipram (1), are discussed.

Phosphodiesterase type IV (PDE IV) inhibition. Synthesis and evaluation of a series of 1,3,4-trisubstituted pyrrolidines

Abstract Structure-activity relationships within a series of 1,3,4-trisubstituted pyrrolidines, novel and selective inhibitors of cAMP-specific phosphodiesterase (PDE IV), are discussed.

CHAPTER 8. CHRONIC PULMONARY INFLAMMATION AND OTHER THERAPEUTIC APPLICATIONS OF PDE IV INHIBITORS

Publisher Summary This chapter discusses some of the important, recent developments in the medicinal chemistry and pharmacology of phosphodiesterase (PDE IV) inhibition. Within the past few years, extensive medicinal chemistry research has resulted in the discovery of potent and selective inhibitors of specific cyclic nucleotide PDEs. Among the PDEs that has received recent attention, PDE IV continues to be an attractive target for the treatment of inflammatory diseases. The attraction of PDE IV inhibition, as a therapy for asthma derives from the potential of elevating cyclic adenosine monophosphate (cAMP) levels, selectively in the airway smooth muscle and the inflammatory cells involved in the asthmatic response. There continues to be significant research in the discovery of novel and selective PDE IV inhibitors. A number of N-substituted derivatives have been prepared and their PDE IV inhibition data have been reported. Carbamate is a representative member of this class and is approximately 10-fold more potent at inhibiting human PDE IV than rolipram. The ability of PDE IV inhibitors to increase intracellular cAMP levels that subsequently inhibits the production and/or release of cytokines, such as TNFα, have led to an increased interest in their use as therapeutic agents for pathologies, in which cytokine over expression and/or deregulation has been implicated. The recently reported positive clinical data, using TNFα-neutralizing antibodies for the treatment of arthritis, has stimulated investigation on the use of PDE IV inhibitors for rheumatoid arthritis. Again, the nonspecific PDE inhibitor has been in clinical trials for the treatment of HIV-infected individuals because of its ability to down-regulate TNFα activity through the inhibition of TNFα synthesis. It is, therefore, likely that selective PDE IV inhibitors, with their ability to suppress TNFα secretion from immune cells must continue to be evaluated for their therapeutic potential.

Synthesis of (±)-plakoridine A lactam

Abstract A stereocontrolled synthesis of plakoridine A lactam, a degradation product of the marine alkaloid plakoridine A, is described.