Molecular pharmacology
January 1, 2003
Barbara J Ebersole, Irache Visiers, Harel Weinstein et al.
72 citations
Indole agonists at the human serotonin 5-HT2A receptor achieve differing efficacies through specific hydrogen-bond interactions with serine residues in helices 3 and 5. Serotonin forms hydrogen bonds with Ser3.36 and Ser5.46; methyl-substitution of the cationic primary amine or the backbone N1-amine disrupts these bonds and reduces efficacy. Mutating Ser3.36 to alanine largely eliminates efficacy differences caused by cationic amine substitution, while mutating Ser5.46 to alanine reduces the efficacy loss from N1-amine substitution. Computational modeling shows these interactions shift the agonist's position in the binding pocket, and the indole ring's position correlates with agonist activity. The findings support a mechanism where agonist position, influenced by specific helix interactions, determines receptor activation, likely shared by other class A G-protein coupled receptors.
Molecular pharmacology
January 1, 1997
B Badio, W L Padgett, J W Daly
52 citations
Ibogaine blocks a specific type of nicotinic receptor channel (ganglionic type) in rat cells, with an IC50 around 20 nM. Its main metabolite, O-des-methylibogaine, is 75 times less potent, and a modified version is 20 times less potent. Ibogaine is much weaker at blocking neuromuscular-type nicotinic receptors. The blockade in rat cells is only partially reversible. In mice, a 10 mg/kg dose of ibogaine completely blocks pain relief caused by epibatidine, which acts through central nicotinic receptors. This effect is gone 24 hours after a 40 mg/kg dose. Blocking these channels may contribute to ibogaine's anti-addictive properties.
Molecular pharmacology
October 17, 2024
Ivone Gomes, Achla Gupta, Elyssa B Margolis et al.
21 citations
Ketamine, a glutamate receptor antagonist developed as an anesthetic over 50 years ago, also acts as a fast-acting antidepressant and analgesic at subanesthetic doses. This study tested ketamine and its metabolites for activity as allosteric modulators of opioid receptors in cell systems and rodent brain. Submicromolar concentrations of ketamine combined with endogenous opioid peptides produced robust synergistic responses at μ, δ, and κ opioid receptors, with S-ketamine showing higher modulatory effects than R-ketamine or racemic ketamine. The metabolite 6-hydroxynorketamine, which does not bind glutamate receptors, showed strong allosteric activity at μ opioid receptors. These findings suggest some therapeutic effects of ketamine are mediated by engaging the endogenous opioid system.
Molecular pharmacology
August 16, 2024
Armida Miranda-Riestra, Montserrat G Cercós, Citlali Trueta et al.
4 citations
Melatonin, a hormone that regulates sleep-wake cycles, also shows antidepressant-like effects in animal studies. These effects appear to involve activation of an enzyme called calcium-calmodulin-dependent kinase II (CaMKII), which plays roles in learning, memory, and brain cell adaptability. Patients with major depression have lower nighttime melatonin levels. This review describes evidence that melatonin may work partly through CaMKII to support neuroplasticity—the brain's ability to form new connections—and that combining melatonin with other antidepressants like ketamine could enhance these benefits.
Molecular pharmacology
January 1, 2026
Lindsay P Cameron, Alaina M Jaster, Raul A Ramos et al.
3 citations
2,5-dimethoxy-4-iodoamphetamine (DOI) is a phenethylamine psychedelic that binds tightly to 5-HT2 receptors, especially 5-HT2A and 5-HT2C. The US Drug Enforcement Administration proposed placing DOI and a similar compound in Schedule I of the Controlled Substances Act, citing their psychoactivity and potential for abuse. This review describes DOI's history, its essential role as a pharmacological tool in over 1,200 publications across five decades, and how it advanced the study of serotonin receptors. It also suggests alternative compounds for studying 5-HT2 receptors if DOI becomes restricted for research.