ACS chemical neuroscience
March 19, 2014
Martin Hansen, Karina Phonekeo, James S Paine et al.
125 citations
Adding a benzyl group to the nitrogen atom of phenethylamine psychedelics like 2C-B greatly increases their binding and activity at serotonin 5-HT2A receptors. A library of 48 compounds with varied phenethylamine and N-benzyl structures was tested. Most had high 5-HT2A affinity; compound 8b showed the highest affinity at 0.29 nM, while 1b was the most functionally potent at 0.074 nM. Selectivity over the related 5-HT2C receptor ranged from 1- to 40-fold in binding, though 6b achieved 100-fold selectivity. Functional selectivity was higher, with 1b exceeding 400-fold selectivity for 5-HT2A.
Journal of Cerebral Blood Flow & Metabolism
April 30, 2014
Anders Ettrup, Sofi Da Cunha‐bang, Brenda Mcmahon et al.
106 citations
A new radioactive tracer, [11C]Cimbi-36, was tested in 29 healthy volunteers for brain imaging using PET scans. This tracer binds to serotonin 2A receptors, which are involved in mood and perception, and is an agonist, meaning it activates the receptor rather than blocking it. High uptake in the brain matched known locations of these receptors. A two-tissue compartment model using arterial blood samples gave the most accurate measurements. In five subjects given a blocker drug (ketanserin), tracer binding decreased in cortical areas but not in the cerebellum, confirming the tracer's specificity and that the cerebellum can serve as a reference region. This is the first agonist PET radioligand to successfully image these receptors in humans.
Bioorganic & medicinal chemistry
July 15, 2015
Martin Hansen, Stine Engesgaard Jacobsen, Shane Plunkett et al.
35 citations
N-Benzyl substitution dramatically alters how phenethylamine 5-HT2A receptor agonists bind to and activate serotonin receptors. This work examined how adding an N-benzyl group to 4-bromo-2,5-dimethoxyphenethylamine derivatives affects affinity for 5-HT2A and 5-HT2C receptors, focusing on the 2' and 3' positions of the benzyl ring. Substitutions at these positions were generally well tolerated. Probing the 2' position with various substituents revealed that small changes profoundly affected affinity, and two ligands lacking a 2'-benzyl substituent unexpectedly showed high affinity, contradicting earlier assumptions. Several high-affinity ligands were tested for functional activity and were less efficacious agonists than previously reported N-benzyl phenethylamines.
Biochemical Pharmacology
April 13, 2020
A. Jensen, A. Halberstadt, Emil Märcher-Rørsted et al.
25 citations
Modifications to specific positions on the 25CN-NBOH molecule, a highly selective 5-HT2A receptor agonist, can retain or reduce its activity. Six new analogs were tested; 3′-methyl and fused-ring variants kept high 5-HT2A receptor activity, while 3′-methoxy and 3′-ethyl versions lost binding and potency. All six analogs showed only partial agonism or antagonism. In mice, 25CN-NBOH and a close analog triggered head-twitch responses (a hallmark of 5-HT2A activation) and reduced marble-burying behavior, suggesting potential benefits for cognitive rigidity disorders. A tritium-labeled version of 25CN-NBOH showed high binding affinity and selectivity for 5-HT2A receptors in rat brain tissue, providing a new tool for future receptor studies.