David I. MaGee

Inhibition of human cholinesterases by drugs used to treat Alzheimer disease.

&NA; Current approaches to the treatment of cognitive and behavioral symptoms of Alzheimer disease emphasize the use of cholinesterase inhibitors. The kinetic effects of the cholinesterase inhibitors donepezil, galantamine, metrifonate, physostigmine, rivastigmine, and tetrahydroaminoacridine were examined with respect to their action on the esterase and aryl acylamidase activities of human acetylcholinesterase (AChE) and human butyrylcholinesterase (BuChE). Each of these drugs inhibited both AChE and BuChE, but to different degrees. Inhibition of BuChE by these compounds was approximately the same, or better, when acetylthiocholine, the analog of the neurotransmitter acetylcholine, was used as the substrate, instead of butyrylthiocholine. In addition, for these drugs, the inhibition of aryl acylamidase activity paralleled that observed for inhibition of esterase activity of AChE and BuChE. Given that drugs that are currently in use for the treatment of Alzheimer disease inhibit both AChE and BuChE, the development of drugs targeted toward the exclusive inhibition of one or the other cholinesterase may be important for understanding the relative importance of inhibition of BuChE and AChE in the treatment of this disease.

Evidence for a Volatile Pheromone in Agrilus planipennis Fairmaire (Coleoptera: Buprestidae) that Increases Attraction to a Host Foliar Volatile

ABSTRACT Analysis by gas chromatography/mass spectrometry (GC/MS) of volatiles from virgin female emerald ash borer, Agrilus planipennis Fairmaire confirmed the emission of (3Z)-lactone [(3Z)-dodecen-12-olide] but not its geometric isomer, (3E)-lactone [(3E)-dodecen-12-olide]. Gas chromatographic/electroantennographic (GC/EAD) analysis of synthetic (3Z)-lactone, which contained 10% (3E) -lactone, showed a strong response of male and female antennae to both isomers. EAG analysis with 0.01 - to100-µg dosages showed a positive dose response, with females giving significantly higher responses than males. In field experiments with sticky purple prism traps, neither lactone isomer affected catches when combined with ash foliar or cortical volatiles (green leaf volatiles or Phoebe oil, respectively). However, on green prism traps, the (3Z)-lactone significantly increased capture of male A. planipennis when traps were deployed in the canopy. Captures of males on traps with both (3E)-lactone and (3Z)-hexenol or with (3Z)-lactone and (3Z)-hexenol were increased by 45–100%, respectively, compared with traps baited with just (3Z)-hexenol. In olfactometer bioassays, males were significantly attracted to (3E) -lactone, but not the (3Z) -lactone or a 60:40 (3E): (3Z) blend. The combination of either (3E)- or (3Z)-lactone with Phoebe oil was not significantly attractive to males. Males were highly attracted to (3Z)-hexenol and the (3Z)-lactone + (3Z)-hexenol combination, providing support for the field trapping results. These data are the first to demonstrate increased attraction with a combination of a pheromone and a green leaf volatile in a Buprestid species.

Ethyl alkynyl ethers: A convenient ketene source for lactone formation

Abstract A convenient and general method for the preparation of lactones of varying size via the intramolecular trapping of a ketene has been developed. Simple thermolysis of various ethoxy acetylene derivatives at 150°C for 2 hours produced the desired compounds in yields ranging from 30%–75%. The addition of tri-n-butylamine was required to achieve reasonable yields for medium and large rings.

Studies on the synthesis of highly substituted furans: The synthesis of calicogorgins A and C

Abstract A short and highly efficient synthesis of calicogorgin A and C has been accomplished. The key features include a rapid assembly of the furanyl moieties, a sulfonyl anion alkylation to join the two halves and a bis-reductive desulfurization.

Contact Sex Pheromones Identified for Two Species of Longhorned Beetles (Coleoptera: Cerambycidae) Tetropium fuscum and T. cinnamopterum in the Subfamily Spondylidinae

ABSTRACT Male Tetropium fuscum (F.) and T. cinnamopterum Kirby mated with live and dead (freeze-killed) conspecific females upon antennal contact, but did not respond to dead females after cuticular waxes were removed by hexane rinsing. Significantly fewer males of each species attempted to copulate with live or dead heterospecific females than with conspecifics, indicating that mate recognition was mediated by species-specific contact sex pheromones in the females cuticular hydrocarbons. GC/MS analysis of T. fuscum elytra identified n-alkanes and mono-methyl branched alkanes of which 11-methylheptacosane and 3- and 5-methyltricosanes were dominant in females. Full male responses, including copulatory behavior, were restored with application of enantiomerically pure synthetic (S)-11-methyl-heptacosane at 40 µg /female (one female equivalent) but not with racemic or (R)-11-methyl-heptacosane. The cuticular hydrocarbons on T. cinnamopterum elytra included 11-methyl-heptacosane as well as n-alkanes, methyl-branched alkanes, mono-alkenes, and (Z, Z)-6, 9-alkadienes. (Z)-9-pentacosene, (Z)-9-heptacosene, and 11-methyl-heptacosane were female dominant, but only (Z)-9-pentacosene elicited precopulatory behaviors in conspecific males at levels similar to those behaviors elicited by unrinsed females, but elicited copulation in fewer than half of males. At female equivalent dosages (10 µg), neither (Z)-9-heptacosene nor (S)-11-methylheptacosane elicited responses in males that were significantly different from those responses to a rinsed female but when applied together, the proportion of males responding was significantly increased. 11-methyl-heptacosene is thus a contact pheromone component common to both species, which may explain the heterospecific mating attempts by some males.

DIRECT FURAN FORMATION BY TREATMENT OF ALKYNYL KETONES WITH STRONG POTASSIUM BASES

Abstract The reaction of keto-alkynes with strong potassium bases such as KOtBu, KHMDS or KH yields substituted furans in moderate to good yields without any special activation of the alkyne required. The method offers both a flexibility and rapid method for the synthesis of di- tri- or tetra-substituted furans, although some yields are only modest at best.

Rapid and facile synthesis of highly substituted furans

Abstract A short and efficient synthesis of highly substituted furans has been accomplished. The method is amenable for the production of 2,5-di, 2,3,5-tri and 2,3,4,5-tetrasubstituted furan compounds containing multiple functionalities.

Combining click-multicomponent reaction: one-pot synthesis of triazolyl methoxy-phenyl indazolo[2,1- b ]phthalazine-trione derivatives

Abstract[(1,2,3-Triazol-4-yl)methoxy-phenyl]-2H-indazolo[2,1-b]phthalazine-trione derivatives were synthesized in a simple and efficient method from the one-pot four-component condensation reaction of phthalhydrazide, aromatic propargyloxy aldehydes, active methylene compounds (dimedone and 1,3-cyclohexanedione), and azides in the presence of Cu(OAc)2/sodium ascorbate and p-toluenesulfonic acid as catalysts in good to excellent yields.

Behavioral and electrophysiological responses of Tetropium fuscum (Coleoptera: Cerambycidae) to pheromone and spruce volatiles.

ABSTRACT The brown spruce longhorn beetle, Tetropium fuscum (F.), is an invasive wood-boring species in eastern Canada. Gas chromatographic/electroantennographic (GC/EAD) analyses of Norway and red spruce volatiles detected a number of consistent EAD-active responses to compounds that are known to be stress-induced in spruce. The effects of these EAD-active compounds on various aspects of adult behavior were tested. In two-choice olfactometer assays, a monoterpene spruce blend, (R) - (-) -linalool, (3Z,6E) -&agr;-farnesene, (E) -&bgr;-farnesene and spruce essential oil were attractive to both sexes. However, when they were combined with the male-produced pheromone (fuscumol), they elicited a sex-specific response: females were significantly attracted to combinations of fuscumol plus either (3Z,6E)-&agr;-farnesene, (E)-&bgr;-farnesene and spruce essential oil but males were not. Fuscumol alone was unattractive to either sex in the olfactometer. Males exposed to fuscumol, (3Z,6E)-&agr;farnesene, or a combination of both, but not (E)-&bgr;-farnesene, were more likely to engage in the pheromone calling posture relative to controls. Both the monoterpene spruce blend and spruce essential oil elicited significantly greater trap capture of both sexes of T. fuscum in the presence of fuscumol and ethanol than (3Z,6E)-&agr;-farnesene or (R)-(-)-linalool, which did not elicit trap capture alone or in combination with fuscumol. The data support the hypothesis that stress-induced sesquiterpene components, such as (3Z,6E)-&agr;-farnesene, are important for mediating close-range attraction and behavior in T. fuscum while the monoterpene components are important for long-range processes (trap capture).

Cholinesterase inhibitors modify the activity of intrinsic cardiac neurons

Cholinesterase inhibitors used to treat the symptoms of Alzheimers disease (AD) inhibit both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), albeit to different degrees. Because central and peripheral neurons, including intrinsic cardiac neurons located on the surface of the mammalian heart, express both BuChE and AChE, we studied spontaneously active intrinsic cardiac neurons in the pig as a model to assess the effects of inhibition of AChE compared to BuChE. Neuroanatomical experiments showed that some porcine intrinsic cardiac neurons expressed AChE and/or BuChE. Enzyme kinetic experiments with cholinesterase inhibitors, namely, donepezil, galantamine, (+/-) huperzine A, metrifonate, rivastigmine, and tetrahydroaminoacridine, demonstrated that these compounds differentially inhibited porcine AChE and BuChE. Donepezil and (+/-) huperzine A were better reversible inhibitors of AChE, and galantamine equally inhibited both the enzymes. Tetrahydroaminoacridine was a better reversible inhibitor of BuChE. Rivastigmine caused more rapid inactivation of BuChE as compared to AChE. Neurophysiological studies showed that acetylcholine and butyrylcholine increase or decrease the spontaneous activity of the intrinsic cardiac neurons. Donepezil, galantamine, (+/-) huperzine A, and tetrahydroaminoacridine changed spontaneous neuronal activity by about 30-35 impulses per minute, while rivastigmine changed it by approximately 100 impulses per minute. It is concluded that (i) inhibition of AChE and BuChE directly affects the porcine intrinsic cardiac nervous system, (ii) the intrinsic cardiac nervous system represents a suitable model for examining the effects of cholinesterase inhibitors on mammalian neurons in vivo, and (iii) the activity of intrinsic cardiac neurons may be affected by pharmacological agents that inhibit cholinesterases.