5-HT2A agonists – University of Copenhagen

Development of selective 5-HT2A agonists

One of the most enigmatic compound classes in the pharmacopeia of psychotropic drugs, the classic psychedelics, have been the subject of scientific investigations of brain function, experimental psychiatry, widespread illicit use, and vast political controversy.

The complex relationship between humans and mind altering drugs has evolved over thousands of years with mescaline (from different species of cacti) and DMT (the active component in Ayahuasca) as prominent examples. Within the western scientific community increasing interest in the healing potential of classic psychedelics, especially psilocybin, has led to numerous promising clinical studies over the decade.

Cimbi-36

In our research we are trying to develop new tool compounds that can help to uncover the mechanism of action of psychedelics. The design, synthesis and biological characterization of novel chemical entities derived from mescaline, has been key in the development of the PET-tracer CIMBI-36” which is currently being used to map serotonin type 2A receptors in the human brain and the discovery of 25CN-NBOH - one of the most selective 5-HT 2A agonists reported in the literature to date.

This endeavour is a collaborative effort between a number of research groups at the University of Copenhagen and international research groups. One of the key goals is the identification of a  selective 5-HT2A receptor agonists suitable for use in clinical studies, in pharmacological doses. 

In 2017 the SAFER project has been launched, where we will be trying to develop functionally selective agonists. For more information see the SAFER website: http://www.safer-itn.eu/


 Publications:

Detailed characterization of the in vitro pharmacological and pharmacokinetic properties of N-(2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine (25CN-NBOH), a highly selective and brain-penetrant 5-HT2A receptor agonist. Jensen, A.A.; McCorvy, J.D.; Leth-Petersen, S.; Bundgaard, C.; Liebscher, G.; Kenakin, T.P.; Brauner-Osborne, H.; Kehler, J.; Kristensen, J.L. JPET 2017, 361, 441-453.

Characterization of the hepatic cytochrome P450 enzymes involved in the metabolism of 25I-NBOMe and 25I-NBOH. L.M. Nielsen, N.B. Holm, S.L.‐Petersen, J.L. Kristensen, L. Olsen, K. Linnet. Drug Test. Analysis. 2017, 9, 671–679.

5-HT2A/5-HT2C Receptor Pharmacology and Intrinsic Clearance of N-Benzylphenethylamines Modified at the Primary Site of Metabolism. Leth-Petersen, S.; Petersen, I.N.; Jensen, A.A.; Bundgaard, C.; Bæk, M.; Kehler, J.; Kristensen, J.L. ACS Chem. Neurosci. 2016, 7, 1614-1619.

Metabolic fate of hallucinogenic NBOMes. Leth-Petersen, S.; Gabel-Jensen, C.; Gillings, Nic.; Lehel, S.; Hansen, H.D.; Knudsen, G.M.; Kristensen, J.L. Chem. Res. Toxicol. 2016, 29, 96-100.

Synthesis and pharmacological evaluation of N-benzyl substituted 4-bromo-2,5-dimethoxyphenethylamines as 5-HT2A/2C partial agonists. Hansen, M.; Jacobsen, S.E.; Plunkett, S.; Liebscher, G.E.; McCorvy, J.D. Bräuner-Osborne, H.; Kristensen, J.L. Bio. Org. Med. Chem. 2015, 23, 3933–3937.

Hallucinogen-like effects of 25CN-NBOH, a novel N-benzylphenethylamine with 100-fold selectivity for 5-HT2A receptors, in mice. Fantegrossi, W.; Gray, B.; Bailey, J.; Smith, D.; Hansen, M.; Kristensen, J.L. Psychopharmacology, 2015, 232(6), 1039-47.

Correlating the Metabolic Stability of Psychedelic 5-HT2A Agonists with Anecdotal Reports of Human Oral Bioavailability. S. Leth-Petersen, C. Bundgaard, M. Hansen, M.A. Carnerup, J. Kehler, J.L. Kristensen. Neurochem. Res. 2014, 39, 2018.

Synthesis and Structure-Activity Relationships of N-Benzyl Phenethylamines as 5-HT2A/2C Agonists. M. Hansen, K. Phonekeo, J.S. Paine, S. Leth-Petersen, M. Begtrup, H. Bräuner-Osborne, J.L. Kristensen. ACS Chem. Neurosci. 2014, 5, 243.

Structure-Activity Relationships of Constrained Phenylethylamine Ligands for the Serotonin 5-HT2 Receptors V. Isberg, J. Paine, S. Leth-Petersen, J.L. Kristensen, D.E. Gloriam. PLoS ONE ,2013, 8(11): e78515.