The selectivity of ��-adrenoceptor agonists at human ��1-, ��2- and ��3-adrenoceptors

Background and purpose:

There are two important properties of receptor–ligand interactions: affinity (the ability of the ligand to bind to the receptor) and efficacy (the ability of the receptor–ligand complex to induce a response). Ligands are classified as agonists or antagonists depending on whether or not they have efficacy. In theory, it is possible to develop selective agonists based on selective affinity, selective intrinsic efficacy or both. This study examined the affinity and intrinsic efficacy of 31 β-adrenoceptor agonists at the three human β-adrenoceptors to determine whether the current agonists are subtype selective because of affinity or intrinsic efficacy.

Experimental approach:

Stable clonal CHO-K1 cell lines, transfected with either the human β₁, β₂ or β₃-adrenoceptor, were used, and whole-cell [³H]-CGP 12177 radioligand binding and [³H]-cAMP accumulation were measured.

Key results:

Several agonists were found to be highly subtype selective because of selective affinity (e.g. salmeterol and formoterol, for the β₂-adrenoceptor over the β₁ or β₃), while others (e.g. isoprenaline) had little affinity–selectivity. However, the intrinsic efficacy of salmeterol, formoterol and isoprenaline was similar across all three receptor subtypes. Other ligands (e.g. denopamine for β₁; clenbuterol, AZ 40140d, salbutamol for β₂) were found to have subtype-selective intrinsic efficacy. Several ligands appeared to activate two agonist conformations of the β₁- and β₃-adrenoceptors.

Conclusions and implications:

There are agonists with subtype selectivity based upon both selective affinity and selective intrinsic efficacy. Therefore, there is scope to develop better selective agonists based upon both selective affinity and selective intrinsic efficacy.This article is commented on by Kenakin, pp. 1045–1047 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2010.00764.x     

��4��2 Nicotinic acetylcholine receptors, willing if able

Li and Steinbach apply nonstationary noise analysis to the whole-cell current responses of low sensitivity α4β2 nAChR stably-expressed in HEK cells. These receptors represent one of the most important nAChR subtypes in brain, and also one of the most difficult to study in native tissues. They found the activating properties of the full agonists ACh and nicotine to be similar with regard to P_open and single channel conductance, whereas the weak α4β2 partial agonist cytisine caused channels to open with low probability but increased single channel conductance. When optimally stimulated by either of the full agonists, approximately 80% of the available receptors opened at the peak of the response. However, comparisons of whole-cell current to estimates of total cell surface receptors, indicated that only about 7% of the total receptor population can be activated. These observations provide important and intriguing new pieces of the brain nicotine receptor puzzle.     

Le diagnostic rapide des mécanismes de résistance aux antibiotiques

Rapid tests using immunologic, biochemical or molecular biology techniques have been introduced for routine diagnosis in the laboratories of microbiology. The development of rapid tests for the detection of antimicrobial resistance mechanisms is justified in patients with high mortality risk when the antimicrobial therapy is unadapted. Rapid tests for detection of beta-lactamase and methicillin-resistance in staphylococci are available for routine use. The development of new molecular techniques for identification coupled with the detection of resistance genes should allow to widely expand the number of resistance mechanisms screened for.     

Low Doses of 17��-Estradiol and 17��-Estradiol Facilitate, Whereas Higher Doses of Estrone and 17��- and 17��-Estradiol Impair, Contextual Fear Conditioning in Adult Female Rats

Estrogens are known to exert significant structural and functional effects in the hippocampus of adult rodents. In particular, 17β-estradiol can improve, impair, or have no effect on hippocampus-dependent learning and memory depending on dose and time of administration. The effects of other forms of estrogen, such as estrone and 17α-estradiol, on hippocampus-dependent learning have not been as thoroughly investigated. Therefore, the purpose of this study was to investigate the effects of 17β-estradiol, estrone, and 17α-estradiol at three different doses on two different tasks: hippocampus-dependent contextual fear conditioning and hippocampus-independent cued fear conditioning. Adult ovariectomized female rats were injected with one of the estrogens at one of the three doses 30 mins before conditioning to assess the rapid effects of these estrogens on acquisition. Twenty-four hours later memory for the context was examined and 1 h later memory for the cue (tone) was assessed. Levels of synaptophysin were examined in the dorsal hippocampus of rats to identify a potential synaptic correlate of hormonal effects on contextual fear conditioning. Low 17β-estradiol and 17α-estradiol enhanced, whereas high 17β-estradiol and 17α-estradiol impaired, contextual fear conditioning. Only the middle dose of estrone severely impaired contextual fear conditioning. Estrogens did not alter performance in the hippocampus-independent cued task. Synaptophysin expression was increased by estrone (at a middle and high dose) and 17β-estradiol (at a middle dose) in the CA3 region of the hippocampus and was not correlated with cognition. The results of this study indicate that estradiol can positively or negatively influence hippocampus-dependent learning and memory, whereas estrone impairs hippocampus-dependent learning and memory in a dose-dependent manner. These results have important therapeutic implications, as estrone, a main component of a widely used hormone replacement therapy, was shown to have either a negative effect or no effect on learning and memory. It may be possible to use 17α-estradiol and lower doses of estrogens as potential alternatives in hormone replacement therapies.     

Über die nikotinartige Wirkung des Cholins,des Azetylcholins und des Cholazyls auf sympathische Ganglienzellen

Zusammenfassung Cholin, Azetylcholin und Cholazyl erregen das Ganglion cerv. sup. der Katze in Konzentrationen, die bei einzelnen Tieren stark schwanken. Es wird eine Methode zur vergleichenden Auswertung solcher Stoffe angegeben. Die chemische Erregung durch Az. Ch. ist die erste Phase der nicotinartigen Wirkung dieses Stoffes, die von einer zweiten, lähmenden Phase gefolgt ist. Die Bedeutung dieses Befundes für die Theorie der chemischen Reizübertragung im Ganglion wird diskutiert.Für ihre wertvolle Hilfe bei der Durchführung der Versuche bin ich den Herren Dr. Hans v. Brücke und Dr. v. Hueber zu großem Dank verpflichtet.Während der Korrektur dieser Arbeit erschien eine Veröffentlichung aus dem Daleschen Laboratorium von Feldberg und Vartiainen (Journ. of Physiol.83, Heft 1, S. 103), die unabhängig von uns zu teilweise identischen Resultaten geführt hat.     

The Le Camus apothecary-grocers in Paris from the XVth to the XVIIth century. Nicolas IV Le Camus owned the Pavillon des Singes in the Rue Saint-Honoré, the residence of the Pocquelin family

Five members of the Le Camus family of Paris were apothecary-grocers, a situation passed down from father to son from the end of the reign of Charles VII up to the reign of Louis XIV, in other words for nearly two centuries. Four of them were called Nicolas and the fifth Jehan. Nicolas I practised his trade in the Rue Saint-Antoine; Nicolas II and Jehan lived in the district of Les Halles, on the corner of the Rue Saint-Denis and the Rue de la Chanvrerie. Nicolas IV was a tenant in a house at the crossroads of the Rue Saint-Honoré and the Rue des Poulies, later absorbed by the opening of the Rue du Louvre. In 1638, Nicolas IV bought the house known as "Le Pavillon des Singes" on the corner of the Rue Saint-Honoré and the Rue des Vieilles Etuves (now the Rue Sauval), the home of the family of Jean Pocquelin, father of Jean-Baptiste, the future Molière. When Nicolas IV died, his goods were divided between his son Fran?ois, lawyer in Parliament, and his daughter Anne who inherited the "Pavillon des Singes". In 1680, she sold it to an administrator of the H?tel-Dieu. Nicolas IV Le Camus was the last Parisian apothecary of this dynasty and no other Le Camus practised pharmacy in Paris until the Royal Declaration of 25th April 1777 which created the College of Pharmacy and the Master of Pharmacy.     

JWH018, a common constituent of ��Spice�� herbal blends, is a potent and efficacious cannabinoid CB1 receptor agonist

Background and purpose:

‘Spice’ is an herbal blend primarily marketed in Europe as a mild hallucinogen with prominent cannabis-like effects and as a legal alternative to cannabis. However, a recent report identified a number of synthetic additives in samples of ‘Spice’. One of these, the indole derivative JWH018, is a ligand for the cannabinoid receptor 1 (CB₁) cannabinoid receptor and inhibits cAMP production in CB₁ receptor-expressing CHO cells. Other effects of JWH018 on CB₁ receptor-mediated signalling are not known, particularly in neurons. Here we have evaluated the signalling pathways activated by JWH018 at CB₁ receptors.

Experimental approach:

We investigated the effects of JWH018 on neurotransmission in cultured autaptic hippocampal neurons. We further analysed its activation of ERK1/2 mitogen activated protein kinase (MAPK) and internalization of CB₁ receptors in HEK293 cells stably expressing this receptor.

Key results:

In cultured autaptic hippocampal neurons, JWH018 potently inhibited excitatory postsynaptic currents (IC₅₀= 14.9 nM) in a concentration- and CB₁ receptor-dependent manner. Furthermore, it increased ERK1/2 MAPK phosphorylation (EC₅₀= 4.4 nM). We also found that JWH018 potently induced rapid and robust CB₁ receptor internalization (EC₅₀= 2.8 nM; t_1/2= 17.3 min).

Conclusions and implications:

JWH018, a prominent component of several herbal preparations marketed for their psychoactivity, is a potent and effective CB₁ receptor agonist that activates multiple CB₁ receptor signalling pathways. Thus, it is likely that the subjective effects of ‘Spice’ are due to activation of cannabinoid CB₁ receptors by JWH018, added to this herbal preparation.