Dataset Information

Methylpiperidinium Iodides as Novel Antagonists for ?7 Nicotinic Acetylcholine Receptors.

ABSTRACT: The ?7 nicotinic acetylcholine receptor (nAChR) is expressed in neuronal and non-neuronal cells and is involved in several physiopathological processes, and is thus an important drug target. We have designed and synthesized novel piperidine derivatives as ?7 nAChR antagonists. Thus, we describe here a new series of 1-[2-(4-alkoxy-phenoxy-ethyl)]piperidines and 1-[2-(4-alkyloxy-phenoxy-ethyl)]-1-methylpiperidinium iodides (compounds 11a-11c and 12a-12c), and their actions on ?7 nAChRs. The pharmacological activity of these compounds was studied in rat CA1 hippocampal interneurons by using the whole-cell voltage-clamp technique. Inhibition of the choline-induced current was less for 11a-11c than for the methylpiperidinium iodides 12a-12c and depended on the length of the aliphatic chain. Those compounds showing strong effects were studied further using molecular docking and molecular dynamics simulations. The strongest and non-voltage dependent antagonism was shown by 12a, which could establish cation-? interactions with the principal (+)-side and van der Waals interactions with the complementary (-)-side in the ?7 nAChRs. Furthermore, compound 11a forms hydrogen bonds with residue Q115 of the complementary (-)-side through water molecules without forming cation-? interactions. Our findings have led to the establishment of a new family of antagonists that interact with the agonist binding cavity of the ?7 nAChR, which represent a promising new class of compounds for the treatment of pathologies where these receptors need to be negatively modulated, including neuropsychiatric disorders as well as different types of cancer.

SUBMITTER: Lopez JJ

PROVIDER: S-EPMC6048275 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Methylpiperidinium Iodides as Novel Antagonists for α7 Nicotinic Acetylcholine Receptors.

López Jhon J JJ García-Colunga Jesús J Pérez Edwin G EG Fierro Angélica A

Frontiers in pharmacology 20180710

The α7 nicotinic acetylcholine receptor (nAChR) is expressed in neuronal and non-neuronal cells and is involved in several physiopathological processes, and is thus an important drug target. We have designed and synthesized novel piperidine derivatives as α7 nAChR antagonists. Thus, we describe here a new series of 1-[2-(4-alkoxy-phenoxy-ethyl)]piperidines and 1-[2-(4-alkyloxy-phenoxy-ethyl)]-1-methylpiperidinium iodides (compounds <b>11a-11c</b> and <b>12a-12c</b>), and their actions on α7 nACh ...[more]

PMID: 30042682

Similar Datasets

Project description:PurposeThe α7 nicotinic acetylcholine receptor (nAChR) is widely expressed in the nervous system, including in the inner retinal neurons in all species studied to date. Although reductions in the expression of α7 nAChRs are thought to contribute to the memory and visual deficits reported in Alzheimer's disease (AD) and schizophrenia , the α7 nAChR knockout (KO) mouse is viable and has only slight visual dysfunction. The absence of a major phenotypic abnormality may be attributable to developmental mechanisms that serve to compensate for α7 nAChR loss. We hypothesized that the upregulation of genes encoding other nAChR subunits or muscarinic acetylcholine receptor (mAChR) subtypes during development partially accounts for the absence of major deficiencies in the α7 nAChR KO mouse. The purpose of this study was to determine whether the deletion of the α7 nAChR subunit in a mouse model resulted in changes in the regulation of other cholinergic receptors or other ion channels in an α7 nAChR KO mouse when compared to a wild-type (WT) mouse.MethodsTo examine gene expression changes, we employed a quantitative real-time polymerase chain reaction (qPCR) using whole retina RNA extracts as well as RNA extracted from selected regions of the retina. These extracts were collected using laser capture microdissection (LCM). The presence of acetylcholine receptor (AChR) subunit and subtype proteins was determined via western blotting. To determine any differences in the number and distribution of choline acetyltransferase (ChAT) amacrine cells, we employed wholemount and vertical immunohistochemistry (IHC) and cell counting. Additionally, in both WT and α7 nAChR KO mouse retinas, the distribution of the nAChR subunit and mAChR subtype proteins were determined via IHC for those KO mice that experienced mRNA changes.ResultsIn the whole retina, there was a statistically significant upregulation of α2, α9, α10, β4, nAChR subunit, and m1 and m4 mAChR subtype transcripts in the α7 nAChR KO mice. However, the retinal layers showed complex patterns of transcript expression. In the ganglion cell layer (GCL), m2 and m4 mAChR subtype transcripts were significantly upregulated, while β3 and β4 nAChR subunit transcripts were significantly downregulated. In the inner portion of the inner nuclear layer (iINL), α2, α9, β4, nAChR subunit, and m3 and m4 mAChR subtype transcripts were significantly downregulated. In the outer portion of the inner nuclear layer (oINL), β2, β4, and m4 AChR subunit transcripts were significantly upregulated. Western blot experiments confirmed the protein expression of α3-α5 and α9-containing nAChR subunits and m1-m2 mAChR subtypes in mouse retinas. IHC results supported many of the mRNA changes observed. Finally, this is the first report of α9 and α10 nAChR subunit expressions in the retina of any species.ConclusionsRather than a simple upregulation of a single AChR subunit or subtype, the absence of the α7 nAChR in the KO mice was associated with complex layer-specific changes in the expression of AChR subunits and subtypes.

Dataset Information

Methylpiperidinium Iodides as Novel Antagonists for ?7 Nicotinic Acetylcholine Receptors.

Publications

Methylpiperidinium Iodides as Novel Antagonists for α7 Nicotinic Acetylcholine Receptors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets