A series of novel aminoalkylindoles was synthesized in an effort to develop compounds that are potent agonists at the CB1 cannabinoid receptor and that are also easily labeled with radioisotopes of iodine for biochemical and imaging studies. 2-Iodophenyl-[1-(1-methylpiperidin-2-ylmethyl)-1H-indol-3-yl]methanone (8, AM2233) had a very high affinity for the rat CB1 receptor, with most of the affinity residing with the (R)-enantiomer. Radioiodinated 8, (R)-8, and (S)-8 were prepared by radioiododestannylation of the tributyltin analogues in high yields, radiochemical purities, and specific radioactivities. In a mouse hippocampal membrane preparation with [131I](R)-8 as radioligand, racemic 8 exhibited a K(i) value of 0.2 nM compared with 1.6 nM for WIN55212-2. In autoradiographic experiments with mouse brain sections, the distribution of radioiodinated 8 was consistent with that of brain CB1 receptors. Again, very little specific binding was seen with the (S)-enantiomer [131I](S)-8 and none occurred with the (R)-enantiomer [131I](R)-8 in sections from CB1 receptor knockout mice. Radioiodinated 8 thus appears to be a suitable radioligand for studies of CB1 cannabinoid receptors.
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http://dx.doi.org/10.1021/jm050135l | DOI Listing |
J Med Chem
December 2024
Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona 08028, Spain.
Activation of cannabinoid CB receptors (CBR) by agonists induces analgesia but also induces cognitive impairment through the heteromer formed between CBR and the serotonin 5HT receptor (5HTR). This side effect poses a serious drawback in the therapeutic use of cannabis for pain alleviation. Peptides designed from the transmembrane helices of CBR, which are predicted to bind 5HTR and alter the stability of the CBR-5HTR heteromer, have been shown to avert CBR agonist-induced cognitive impairment while preserving analgesia.
View Article and Find Full Text PDFImmunopharmacol Immunotoxicol
December 2024
Pharmacology Department, Medical Research and Clinical Studies Institute, National Research Center, Cairo, Egypt.
Background: Ulcerative colitis (UC) is a frequent inflammatory bowel disease (IBD) that causes long-lasting inflammation in the innermost lining of the rectum and colon.
Objective: The aim of this study was to evaluate the therapeutic effect of () on the amelioration of acetic acid-induced colitis in rats.
Materials And Methods: Group 1: normal control group was intrarectally administered saline solution (0.
Biophys Chem
December 2024
Tecnologico de Monterrey, The Institute for Obesity Research, Unit of Experimental Medicine, Monterrey, NL 64849, Mexico. Electronic address:
The cannabinoid receptor 1 (CB1) is an essential component of the endocannabinoid system, responsible for regulating various physiological processes such as pain, mood, and appetite. Despite increasing interest in the therapeutic potential of CB1 modulators, the precise mechanisms by which small molecules modulate receptor activity-particularly without fully transitioning between active and inactive states-remain partially understood. In this study, the complexity of CB1-ligand interactions was evaluated for the inactive CB1 state.
View Article and Find Full Text PDFBehav Pharmacol
December 2024
Department of Psychology, Grand Valley State University, Allendale, Michigan, USA.
Recent evidence suggests that cannabis can impair simple auditory processes, and these alterations might be due to cannabinoid agonism. The effect of cannabinoid agonism on relatively complex processes such as auditory discrimination is unknown. The goal of this study was to examine the impact of WIN 55,212-2, a CB1 receptor and CB2 receptor agonism, on auditory discrimination using a go/no-go task.
View Article and Find Full Text PDFBrain Res
December 2024
Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil.
Numerous studies have explored the role of cannabinoids in neurological conditions, chronic pain and neurodegenerative diseases. Restoring autophagy has been proposed as a potential target for the treatment of neurodegenerative diseases. In our study, we used a neuroblastoma cell line that overexpresses wild-type α-synuclein to investigate the effects of cannabidiol on autophagy modulation and reduction in the level of cytosolic α-synuclein.
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