The discovery of indazapyroxamet: a novel 3-pyridinyl insecticide targeting piercing/sucking insects.

In recent years, the registrations for a number of commercial insecticides utilized for piercing/sucking insects have been cancelled or restricted. To meet this growing need for new hemipteran controlling agrochemicals, we discovered a 2-(pyridin-3-yl)-thiazole compound, with limited insecticidal activity against cotton/melon aphid (Aphis gossypii). The 2-(pyridin-3-yl)-thiazole moiety offered us a basis to pursue the bicyclic 2-(pyridin-3-yl)-2H-indazole carboxamides.

Discovery of novel (N-aryl-4-methylpiperidinyl)pyrazoles: a new class of potent lepidopteran insecticides.

Background: Insects of the order Lepidoptera are among the most destructive global pests, causing billions of dollars in damage annually. A new class of N-arylpyrazole-4-methylpiperidines with potent activity on lepidopteran species has been discovered.

Results: In a high-throughput insecticide screen compound 1 was identified to possess modest activity on the lepidopteran insect Plutella xylostella.

Structure-Activity Relationships for a Series of (Bis(4-fluorophenyl)methyl)sulfinyl Alkyl Alicyclic Amines at the Dopamine Transporter: Functionalizing the Terminal Nitrogen Affects Affinity, Selectivity, and Metabolic Stability.

Atypical dopamine transporter (DAT) inhibitors have shown therapeutic potential in preclinical models of psychostimulant abuse. In rats, 1-(4-(2-((bis(4-fluorophenyl)methyl)sulfinyl)ethyl)-piperazin-1-yl)-propan-2-ol () was effective in reducing the reinforcing effects of both cocaine and methamphetamine but did not exhibit psychostimulant behaviors itself. While further development of is ongoing, diastereomeric separation, as well as improvements in potency and pharmacokinetics were desirable for discovering pipeline drug candidates.

A Novel Bromine-Containing Paroxetine Analogue Provides Mechanistic Clues for Binding Ambiguity at the Central Primary Binding Site of the Serotonin Transporter.

The serotonin transporter (SERT) is the primary target for the selective serotonin reuptake inhibitors (SSRIs). However, the structural basis for the extraordinarily high binding affinity of the widely prescribed SSRI, paroxetine, to human SERT (hSERT) has not yet been fully elucidated. Our previous findings unveiled a plausible ambiguity in paroxetine's binding orientations that may constitute an integral component of this SSRI's high affinity for hSERT.

Effects of ( R)-Modafinil and Modafinil Analogues on Dopamine Dynamics Assessed by Voltammetry and Microdialysis in the Mouse Nucleus Accumbens Shell.

Recent discoveries have improved our understanding of the physiological and pathological roles of the dopamine transporter (DAT); however, only a few drugs are clinically available for DAT-implicated disorders. Among those drugs, modafinil (MOD) and its ( R)-enantiomer (R-MOD) have been used off-label as therapies for psychostimulant use disorders, but they have shown limited effectiveness in clinical trials. Recent preclinical studies on MOD and R-MOD have led to chemically modified structures aimed toward improving their neurobiological properties that might lead to more effective therapeutics for stimulant use disorders.

Distinct effects of (R)-modafinil and its (R)- and (S)-fluoro-analogs on mesolimbic extracellular dopamine assessed by voltammetry and microdialysis in rats.

Psychostimulant use disorders remain an unabated public health concern worldwide, but no FDA approved medications are currently available for treatment. Modafinil (MOD), like cocaine, is a dopamine reuptake inhibitor and one of the few drugs evaluated in clinical trials that has shown promise for the treatment of cocaine or methamphetamine use disorders in some patient subpopulations. Recent structure-activity relationship and preclinical studies on a series of MOD analogs have provided insight into modifications of its chemical structure that may lead to advancements in clinical efficacy.

Computation-guided analysis of paroxetine binding to hSERT reveals functionally important structural elements and dynamics.

The serotonin transporter (SERT) is one of the primary targets for medications to treat neuropsychiatric disorders and functions by exploiting pre-existing ion gradients of Na, Cl, and K to translocate serotonin from the synaptic cleft into the presynaptic neuron. Although recent hSERT crystal structures represent a milestone for structure-function analyses of mammalian neurotransmitter:sodium symporters, they are all derived from thermostabilized but transport-deficient constructs. Two of these structures are in complex with paroxetine, the most potent selective serotonin reuptake inhibitor known.

Effects of the nicotinic agonist varenicline, nicotinic antagonist r-bPiDI, and DAT inhibitor (R)-modafinil on co-use of ethanol and nicotine in female P rats.

Rationale: Co-users of alcohol and nicotine are the largest group of polysubstance users worldwide. Commonalities in mechanisms of action for ethanol (EtOH) and nicotine proposes the possibility of developing a single pharmacotherapeutic to treat co-use.

Objectives: Toward developing a preclinical model of co-use, female alcohol-preferring (P) rats were trained for voluntary EtOH drinking and i.

Atypical dopamine transporter inhibitors attenuate compulsive-like methamphetamine self-administration in rats.

Methamphetamine (METH) is a highly addictive drug, but no pharmacological treatment is yet available for METH use disorders. Similar to METH, the wake-promoting drug (R)-modafinil (R-MOD) binds to the dopamine transporter (DAT). Unlike METH, R-MOD is not a substrate for transport by DAT and has low abuse potential.

Novel and High Affinity 2-[(Diphenylmethyl)sulfinyl]acetamide (Modafinil) Analogues as Atypical Dopamine Transporter Inhibitors.

The development of pharmacotherapeutic treatments of psychostimulant abuse has remained a challenge, despite significant efforts made toward relevant mechanistic targets, such as the dopamine transporter (DAT). The atypical DAT inhibitors have received attention due to their promising pharmacological profiles in animal models of cocaine and methamphetamine abuse. Herein, we report a series of modafinil analogues that have an atypical DAT inhibitor profile.

Using click chemistry toward novel 1,2,3-triazole-linked dopamine D3 receptor ligands.

The dopamine D3 receptor (D3R) is a target of pharmacotherapeutic interest in a variety of neurological disorders including schizophrenia, Parkinson's disease, restless leg syndrome, and drug addiction. A common molecular template used in the development of D3R-selective antagonists and partial agonists incorporates a butylamide linker between two pharmacophores, a phenylpiperazine moiety and an extended aryl ring system. The series of compounds described herein incorporates a change to that chemical template, replacing the amide functional group in the linker chain with a 1,2,3-triazole group.

R-modafinil attenuates nicotine-taking and nicotine-seeking behavior in alcohol-preferring rats.

(±)-Modafinil (MOD) is used clinically for the treatment of sleep disorders and has been investigated as a potential medication for the treatment of psychostimulant addiction. However, the therapeutic efficacy of (±)-MOD for addiction is inconclusive. Herein we used animal models of self-administration and in vivo microdialysis to study the pharmacological actions of R-modafinil (R-MOD) and S-modafinil (S-MOD) on nicotine-taking and nicotine-seeking behavior, and mechanisms underlying such actions.

Malaria-infected mice live until at least day 30 after a new artemisinin-derived thioacetal thiocarbonate combined with mefloquine are administered together in a single, low, oral dose.

In only three steps and in 21-67% overall yields from the natural trioxane artemisinin, a series of 21 new trioxane C-10 thioacetals was prepared. Upon receiving a single oral dose of only 6 mg/kg of the monomeric trioxane 12c combined with 18 mg/kg of mefloquine hydrochloride, Plasmodium berghei-infected mice survived on average 29.8 days after infection.

Clinical outcomes following radial versus femoral artery access in primary or rescue percutaneous coronary intervention in Scotland: retrospective cohort study of 4534 patients.

Objective: To assess short-term and medium-term outcomes following radial and femoral artery access for primary or rescue percutaneous coronary intervention (PCI).

Design: Retrospective cohort study.

Setting: Scotland-wide.

Malaria-infected mice are completely cured by one 6 mg/kg oral dose of a new monomeric trioxane sulfide combined with mefloquine.

Sixteen new anilide derivatives of the natural trioxane artemisinin were prepared and evaluated for antimalarial efficacy in Plasmodium berghei infected mice. Of these 16 new anilides administered orally as one 6 mg/kg dose combined with 18 mg/kg mefloquine hydrochloride, only sulfide 3-arteSanilide 12d was completely curative: on day 30 after infection, all mice in this group had no detectable parasitemia, gained as much weight as the uninfected control mice, and behaved normally.

Behavioral sensitization to 3,4-methylenedioxymethamphetamine is long-lasting and modulated by the context of drug administration.

To begin to characterize the temporal profile of behavioral sensitization to the amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA), rats were treated with either saline or MDMA (5.0 mg/kg) twice daily for 5 days, followed by a challenge injection of MDMA (2.5 mg/kg) either 15 or 100 days later.

Perioperative and long-term outcomes following aortic valve replacement: a population cohort study of 4124 consecutive patients.

Objective: Because of increasing life expectancy, more patients require valve replacement for aortic stenosis. We aimed to determine perioperative and long-term outcomes, the factors associated with these and whether they have changed over time.

Methods: We undertook a retrospective cohort study of all 4124 patients, who underwent isolated, primary aortic valve replacement in Scotland between April 1996 and March 2009 inclusive.

Percutaneous coronary intervention in the elderly: changes in case-mix and periprocedural outcomes in 31,758 patients treated between 2000 and 2007.

Background: The elderly account for an increasing proportion of the population and have a high prevalence of coronary heart disease. Percutaneous coronary intervention (PCI) is the most common method of revascularization in the elderly. We examined whether the risk of periprocedural complications after PCI was higher among elderly (age > or =75 years) patients and whether it has changed over time.

Previous coronary stent implantation and cardiac events in patients undergoing noncardiac surgery.

Background: Noncardiac surgery performed after coronary stent implantation is associated with an increased risk of stent thrombosis, myocardial infarction, and death. The influence of stent type and period of risk still have to be defined.

Methods And Results: We linked the Scottish Coronary Revascularisation Register with hospital admission data to undertake a Scotland-wide retrospective cohort study examining cardiac outcomes in all patients who received drug-eluting or bare-metal stents between April 2003 and March 2007 and subsequently underwent noncardiac surgery.

Obesity paradox in a cohort of 4880 consecutive patients undergoing percutaneous coronary intervention.

Aims: We sought to investigate the impact of body mass index (BMI) on long-term all-cause mortality in patients following first-time elective percutaneous coronary intervention (PCI).

Methods And Results: We used the Scottish Coronary Revascularisation Register to undertake a cohort study of all patients undergoing elective PCI in Scotland between April 1997 and March 2006 inclusive. We excluded patients who had previously undergone revascularization.

Drug-eluting stents versus bare-metal stents for off-label indications: a propensity score-matched outcome study.

Background: The US Food and Drug Administration recently concluded that data on off-label drug-eluting stent (DES) safety are limited. However, in actual clinical practice, DES are often used for off-label indications, and observational studies demonstrate that complications are higher when compared with on-label use. We aimed to determine whether clinical outcomes differ after DES and bare-metal stent implantation in a patient cohort defined by DES off-label indications.

Hospital and operator variations in drug-eluting stent use: a multi-level analysis of 5967 consecutive patients in Scotland.

Objective: To determine whether drug-eluting stent (DES) use varies among Scottish hospitals, and the extent to which any variations are explained by differences between operators, patients and lesions.

Methods: Multi-level analysis of consecutive patients treated with percutaneous coronary intervention (PCI) between April 2005 and March 2006 in Scotland, using the Scottish Coronary Revascularization Registry.

Results: A total of 38 operators performed 5967 PCI procedures on 8489 lesions.

Synthesis and in vitro protozoocidal evaluation of novel diazabicyclic tropolone derivatives.

The synthesis and in vitro antiparasitic activity of twenty-seven novel diazabicycles based on tropolone ethers is presented. The compounds can be readily prepared by means of a high-yielding hetero Diels-Alder reaction using simple and readily available starting materials. Several of the new diazabicycles have in vitro activities against Trypanosoma cruzi, Leishmania donovani, Trypanosoma brucei rhodesiense, and chloroquine-resistant Plasmodium falciparum that are comparable or superior to those of currently employed protozoocidal agents.