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1.
ACS Chem Neurosci ; 15(7): 1501-1514, 2024 04 03.
Article in English | MEDLINE | ID: mdl-38511291

ABSTRACT

NS9283, 3-(3-pyridyl)-5-(3-cyanophenyl)-1,2,4-oxadiazole, is a selective positive allosteric modulator of (α4)3(ß2)2 nicotinic acetylcholine receptors (nAChRs). It has good subtype selective therapeutic potential afforded by its specific binding to the unique α4-α4 subunit interface present in the (α4)3(ß2)2 nAChR. However, there is currently a lack of structure activity relationship (SAR) studies aimed at developing a class of congeners endowed with the same profile of activity that can help consolidate the druggability of the α4-α4 subunit interface. In this study, new NS9283 analogues were designed, synthesized, and characterized for their ability to selectively potentiate the ACh activity at heterologous (α4)3(ß2)2 nAChRs vs nAChR subtypes (α4)2(ß2)3, α5α4ß2, and α7. With few exceptions, all the NS9283 analogues exerted positive modulation of the (α4)3(ß2)2 nAChR ACh-evoked responses. Above all, those modified at the 3-cyanophenyl moiety by replacement with 3-nitrophenyl (4), 4-cyanophenyl (10), and N-formyl-4-piperidinyl (20) showed the same efficacy as NS9283, although with lower potency. Molecular dynamics simulations of NS9283 and some selected analogues highlighted consistency between potentiation activity and pose of the ligand inside the α4-α4 site with the main interaction being with the complementary (-) side and induction of a significant conformational change of the Trp156 residue in the principal (+) side.


Subject(s)
Receptors, Nicotinic , Receptors, Nicotinic/metabolism , Pyridines/pharmacology , Pyridines/chemistry , Cell Membrane/metabolism , Oxadiazoles/pharmacology
2.
J Med Chem ; 66(1): 306-332, 2023 01 12.
Article in English | MEDLINE | ID: mdl-36526469

ABSTRACT

Modifications of the cationic head and the ethylene linker of 2-(triethylammonium)ethyl ether of 4-stilbenol (MG624) have been proved to produce selective α9*-nAChR antagonism devoid of any effect on the α7-subtype. Here, single structural changes at the styryl portion of MG624 lead to prevailing α7-nAChR antagonism without abolishing α9*-nAChR antagonism. Nevertheless, rigidification of the styryl into an aromatic bicycle, better if including a H-bond donor NH, such as 5-indolyl (31), resulted in higher and more selective α7-nAChR affinity. Hybridization of this modification with the constraint of the 2-triethylammoniumethyloxy portion into (R)-N,N-dimethyl-3-pyrrolidiniumoxy substructure, previously reported as the best modification for the α7-nAChR affinity of MG624 (2), was a winning strategy. The resulting hybrid 33 had a subnanomolar α7-nAChR affinity and was a potent and selective α7-nAChR antagonist, producing at the α7-, but not at the α9*-nAChR, a profound loss of subsequent ACh function.


Subject(s)
Receptors, Nicotinic , Ether , alpha7 Nicotinic Acetylcholine Receptor , Ethyl Ethers , Ethers
3.
J Med Chem ; 65(14): 10079-10097, 2022 07 28.
Article in English | MEDLINE | ID: mdl-35834819

ABSTRACT

Nicotinic acetylcholine receptors containing α9 subunits (α9*-nAChRs) are potential druggable targets arousing great interest for pain treatment alternative to opioids. Nonpeptidic small molecules selectively acting as α9*-nAChRs antagonists still remain an unattained goal. Here, through modifications of the cationic head and the ethylene linker, we have converted the 2-triethylammonium ethyl ether of 4-stilbenol (MG624), a well-known α7- and α9*-nAChRs antagonist, into some selective antagonists of human α9*-nAChR. Among these, the compound with cyclohexyldimethylammonium head (7) stands out for having no α7-nAChR agonist or antagonist effect along with very low affinity at both α7- and α3ß4-nAChRs. At supra-micromolar concentrations, 7 and the other selective α9* antagonists behaved as partial agonists at α9*-nAChRs with a very brief response, followed by rebound current once the application is stopped and the channel is disengaged. The small or null postapplication activity of ACh seems to be related to the slow recovery of the rebound current.


Subject(s)
Ammonium Compounds , Receptors, Nicotinic , Ammonium Compounds/pharmacology , Ether , Humans , Nicotinic Antagonists/pharmacology , Quaternary Ammonium Compounds , Stilbenes
4.
Bioorg Med Chem Lett ; 65: 128701, 2022 06 01.
Article in English | MEDLINE | ID: mdl-35346843

ABSTRACT

A series of racemic benzofurans bearing N-methyl-2-pyrrolidinyl residue at C(2) or C(3) has been synthesized and tested for affinity at the α4ß2 and α3ß4 nicotine acetylcholine receptors (nAChRs). As previously reported for the benzodioxane based analogues, hydroxylation at proper position of benzene ring results in high α4ß2 nAChR affinity and α4ß2 vs. α3ß4 nAChR selectivity. 7-Hydroxy-N-methyl-2-pyrrolidinyl-1,4-benzodioxane (2) and its 7- and 5-amino benzodioxane analogues 3 and 4, which are all α4ß2 nAChR partial agonists, and 2-(N-methyl-2-pyrrolidinyl)-6-hydroxybenzofuran (12) were selected for functional characterization at the two α4ß2 stoichiometries, the high sensitivity (α4)2(ß2)3 and the low sensitivity (α4)3(ß2)2. The benzene pattern substitution, which had previously been found to control α4ß2 partial agonist activity and α4ß2 vs. α3ß4 selectivity, proved to be also involved in stoichiometry-selectivity. The 7-hydroxybenzodioxane derivative 2 selectively activates (α4)2(ß2)3 nAChR, which cannot be activated by its 5-amino analogue 4. A marginal structural modification, not altering the base pyrrolidinyl benzodioxane scaffold, resulted in opposite activity profiles at the two α4ß2 nAChR isoforms providing an interesting novel case study.


Subject(s)
Benzofurans , Receptors, Nicotinic , Benzene , Benzofurans/pharmacology , Ligands , Nicotinic Agonists/chemistry , Receptors, Nicotinic/chemistry
5.
J Org Chem ; 86(21): 15712-15716, 2021 11 05.
Article in English | MEDLINE | ID: mdl-34643386

ABSTRACT

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 NaH2PO4/Na2HPO4 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.


Subject(s)
Ketones , Water , Lactones , Oxidation-Reduction , Sulfuric Acids
6.
Molecules ; 26(12)2021 Jun 12.
Article in English | MEDLINE | ID: mdl-34204637

ABSTRACT

The selectivity of α4ß2 nAChR agonists over the α3ß4 nicotinic receptor subtype, predominant in ganglia, primarily conditions their therapeutic range and it is still a complex and challenging issue for medicinal chemists and pharmacologists. Here, we investigate the determinants for such subtype selectivity in a series of more than forty α4ß2 ligands we have previously reported, docking them into the structures of the two human subtypes, recently determined by cryo-electron microscopy. They are all pyrrolidine based analogues of the well-known α4ß2 agonist N-methylprolinol pyridyl ether A-84543 and differ in the flexibility and pattern substitution of their aromatic portion. Indeed, the direct or water mediated interaction with hydrophilic residues of the relatively narrower ß2 minus side through the elements decorating the aromatic ring and the stabilization of the latter by facing to the not conserved ß2-Phe119 result as key distinctive features for the α4ß2 affinity. Consistently, these compounds show, despite the structural similarity, very different α4ß2 vs. α3ß4 selectivities, from modest to very high, which relate to rigidity/extensibility degree of the portion containing the aromatic ring and to substitutions at the latter. Furthermore, the structural rationalization of the rat vs. human differences of α4ß2 vs. α3ß4 selectivity ratios is here proposed.


Subject(s)
Nicotinic Agonists/chemistry , Receptors, Nicotinic/ultrastructure , Animals , Binding Sites , Cryoelectron Microscopy/methods , Databases, Genetic , Humans , Ligands , Molecular Docking Simulation , Nicotinic Agonists/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Rats , Receptors, Nicotinic/metabolism , Structure-Activity Relationship , Synaptic Transmission/drug effects
7.
Carbohydr Res ; 499: 108229, 2021 Jan.
Article in English | MEDLINE | ID: mdl-33401228

ABSTRACT

Heterogeneous solid catalysis by the commercially available perfluorosulfonic ionomer Aquivion-H allowed 1,2:5,6-diacetonide of d-mannitol (1), immediate precursor of important unichiral C3-synthons, to be efficiently obtained from d-mannitol and 2,2-dimethoxypropane in DMF at room temperature. The 1,2-monoacetonide, whose intermediate formation is the rate-limiting step, could be almost completely converted into 1 with limited concurrent transformation of 1 into triacetonides. In line with recent literature reports, these results indicate that heterogeneous catalysis by Aquivion-H surpasses the performances of homogeneous acidic catalysis assuring, presumably for its peculiar morphology, a higher product selectivity. Easy recovery at the end of the reaction and recyclability are additional advantages of this solid acid catalyst.


Subject(s)
Glucocorticoids/chemistry , Mannitol/chemistry , Catalysis , Molecular Conformation
8.
J Med Chem ; 63(24): 15668-15692, 2020 12 24.
Article in English | MEDLINE | ID: mdl-33325696

ABSTRACT

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 α4ß2 and α3ß4 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 α4ß2/α3ß4 selectivity to the α4ß2 partial agonism. Docking into the two receptor structures recently determined by cryo-electron microscopy and site-directed mutagenesis at the minus ß2 side converge in indicating that the limited accommodation capacity of the ß2 pocket, compared to that of the ß4 pocket, makes substitution at C(5) rather than at more projecting C(7) position determinant for this pursued subtype selectivity.


Subject(s)
Dioxanes/chemistry , Nicotinic Agonists/chemistry , Receptors, Nicotinic/chemistry , Binding Sites , Cryoelectron Microscopy , Dioxanes/chemical synthesis , Dioxanes/metabolism , Humans , Hydrogen Bonding , Molecular Docking Simulation , Mutagenesis, Site-Directed , Nicotinic Agonists/chemical synthesis , Nicotinic Agonists/metabolism , Nicotinic Antagonists/chemistry , Nicotinic Antagonists/metabolism , Pyrrolidines/chemistry , Receptors, Nicotinic/genetics , Receptors, Nicotinic/metabolism , Stereoisomerism , Structure-Activity Relationship
9.
Eur J Med Chem ; 200: 112419, 2020 Aug 15.
Article in English | MEDLINE | ID: mdl-32502862

ABSTRACT

1,4-Benzodioxane has long been a versatile template widely employed to design molecules endowed with diverse bioactivities. Its use spans the last decades of medicinal chemistry until today concerning many strategies of drug discovery, not excluding the most advanced ones. Here, more than fifty benzodioxane-related lead compounds, selected from recent literature, are presented showing the different approaches with which they have been developed. Agonists and antagonists at neuronal nicotinic, α1 adrenergic and serotoninergic receptor subtypes and antitumor and antibacterial agents form the most representative classes, but a variety of other biological targets are addressed by benzodioxane-containing compounds.


Subject(s)
Dioxanes/chemistry , Drug Design , Animals , Chemistry, Pharmaceutical/methods , Humans
10.
Psychopharmacology (Berl) ; 237(8): 2317-2326, 2020 Aug.
Article in English | MEDLINE | ID: mdl-32382782

ABSTRACT

RATIONALE: Prolinol aryl ethers and their rigidified analogues pyrrolidinyl benzodioxanes have a high affinity for mammalian α4ß2 nicotinic acetylcholine receptors (nAChRs). Electrophysiological studies have shown that the former are full agonists and the latter partial agonists or antagonists of human α4ß2 receptors, but their in vivo effects are unknown. OBJECTIVES AND METHODS: As α4ß2 nAChRs play an important role in the 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. RESULTS: In 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 dose-response 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 [3H]-epibatidine receptors than [125I]-αBungarotoxin 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 agonist-induced activities.


Subject(s)
Maze Learning/drug effects , Nicotinic Agonists/metabolism , Nicotinic Antagonists/metabolism , Pyrrolidines/metabolism , Receptors, Nicotinic/metabolism , Animals , Dose-Response Relationship, Drug , Ethers/metabolism , Ethers/pharmacology , Female , Male , Maze Learning/physiology , Morphinans/metabolism , Morphinans/pharmacology , Nicotine/metabolism , Nicotine/pharmacology , Nicotinic Agonists/pharmacology , Nicotinic Antagonists/pharmacology , Pyrrolidines/pharmacology , Pyrrolidinones/metabolism , Pyrrolidinones/pharmacology , Zebrafish
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