Nicotinic acetylcholine receptors containing α9 subunits (α9*-nAChRs) are potential druggable targets arousing great interest within the nicotinic receptor family with a special focus on a pain treatment alternative to opioids. Non-peptidic small molecules selectively acting as antagonists at this receptor subtype, especially without any effect on the closely related α7-nAChR, still remain an unattained goal, the achievement of which would provide invaluable tools to validate such an approach. Here, through relatively few directed modifications of the cationic head and the ethylene linker, we have converted the 2-triethylammonium ethyl ether of 4-stilbenol (MG624), a well-known antagonist for both α7 and α9* receptors, into a set of selective antagonists of human α9*-nAChR.Among these, the compound with cyclohexyldimetylammonium head (7) stands out for having no agonist or antagonist effect at α7-nAChR along with very low binding affinity at both α7 and α3β4 nicotinic receptor subtypes. Applied alone at high supra-micromolar concentrations, 7 and the other selective α9* antagonists behaved as partial agonists at α9*-nAChRs with a very short duration of the response, most likely due to very rapid block of the open channel, as revealed by the occurrence of rebound current once the application is stopped and the channel is disengaged. The small (nearly null in the case of 7) post-application residual activity of ACh control stimulation seems to be related to the slow recovery of the rebound current.
A series of diastereomeric
2-(2-pyrrolidinyl)-1,4-benzodioxanes
bearing a small, hydrogen-bonding substituent at the 7-, 6-, or 5-position
of benzodioxane have been studied for α4β2 and α3β4
nicotinic acetylcholine receptor affinity and activity. Analogous
to C(5)H replacement with N and to a much greater extent than decoration
at C(7), substitution at benzodioxane C(5) confers very high α4β2/α3β4
selectivity to the α4β2 partial agonism. Docking into
the two receptor structures recently determined by cryo-electron microscopy
and site-directed mutagenesis at the minus β2 side converge
in indicating that the limited accommodation capacity of the β2
pocket, compared to that of the β4 pocket, makes substitution
at C(5) rather than at more projecting C(7) position determinant for
this pursued subtype selectivity.
RationaleProlinol aryl ethers and their rigidified analogues pyrrolidinyl benzodioxanes have a high affinity for mammalian a4β2 nicotinic acetylcholine receptors (nAChRs). Electrophysiological studies have shown that the former are full agonists and the latter partial agonists or antagonists of human a4β2 receptors, but their in vivo effects are unkown.
Objectives and MethodsAs a4b2 nAChRs play an important role in cognition and the rewarding effects of nicotine we tested the effects of two full agonists and one antagonist on spatial learning, memory and attention in zebrafish using a T-maze task and virtual object recognition test (VORT).The effect of a partial agonist in reducing nicotine-induced conditioned place preference (CPP), was also investigated.
ResultsIn comparison with the vehicle alone, the full agonists MCL-11 and MCL-28 induced a significant cognitive enhancement as measured by the reduced running time in the T-maze and increased attention as measured by the increased discrimination index in the VORT. MCL-11 was 882 times more potent than nicotine. The two compounds were characterised by an inverted U-shaped doseresponse curve, and their effects were blocked by the co-administration of the antagonist MCL-117, which alone had no effect. The partial agonist MCL-54 induced CPP and had an inverted U-shaped dose-response curve similar to that of nicotine, but blocked the reinforcing effect of co-administered nicotine. Binding studies showed that all of the compounds have a higher affinity for heteromeric [ 3 H]epibatidine receptors than [ 125 I]-aBungarotoxin receptors. MCL-11 was the most selective of heteromeric receptors.
Conclusions.These behavioural studies indicate that full-agonist prolinol aryl ethers, are very active in increasing spatial learning, memory and attention in zebrafish. The benzodioxane partial agonist MCL-54 reduced nicotine-induced CPP, and the benzodioxane antagonist MCL-117 blocked all agonistinduced activities.
Cyclic ketones were quickly and quantitatively converted to 5-, 6-, and 7-membered lactones, very important synthons, by treatment with Oxone, a cheap, stable, and nonpollutant oxidizing reagent, in 1 M NaH 2 PO 4 /Na 2 HPO 4 water solution (pH 7). Under such simple and green conditions, no hydroxyacid was formed, thus making the adoption of more complex and non-eco-friendly procedures previously developed to avoid lactone hydrolysis unnecessary. With some changes, the method was successfully applied also to water-insoluble ketones such as adamantanone, acetophenone, 2-indanone, and the challenging cycloheptanone.
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