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5-HT2A Receptor

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David E Nichols – One of the best experts on this subject based on the ideXlab platform.

  • assessment of the roles of serines 5 43 239 and 5 46 242 for binding and potency of agonist ligands at the human serotonin 5 ht2a Receptor
    Molecular Pharmacology, 2007
    Co-Authors: Michael R Braden, David E Nichols


    We assessed the relative importance of two serine residues located near the top of transmembrane helix 5 of the human 5-HT2A Receptor, comparing the wild type with S5.43(239)A or S5.46(242)A mutations. Using the ergoline lysergic acid diethylamide (LSD), and a series of substituted tryptamine and phenethylamine 5-HT2A Receptor agonists, we found that Ser5.43(239) is more critical for agonist binding and function than Ser5.46(242). Ser5.43(239) seems to engage oxygen substituents at either the 4- or 5-position of tryptamine ligands and the 5-position of phenylalkylamine ligands. Even when a direct binding interaction cannot occur, our data suggest that Ser5.43(239) is still important for Receptor activation. Polar ring-substituted tryptamine ligands also seem to engage Ser5.46(242), but tryptamines lacking such a substituent may adopt an alternate binding orientation that does not engage this residue. Our results are consistent with the role of Ser5.43(239) as a hydrogen bond donor, whereas Ser5.46(242) seems to serve as a hydrogen bond acceptor. These results are consistent with the functional topography and utility of our in silico-activated homology model of the h5-HT2A Receptor. In addition, being more distal from the absolutely conserved Pro5.50, a strong interaction with Ser5.43(239) may be more effective in straightening the kink in helix 5, a feature that is possibly common to all type A GPCRs that have polar residues at position 5.43.

  • c 4 5 6 trimethoxyindan 1 yl methanamine a mescaline analogue designed using a homology model of the 5 ht2a Receptor
    Journal of Medicinal Chemistry, 2006
    Co-Authors: Thomas H Mclean, James J Chambers, Jason C Parrish, Michael R Braden, Danuta Maronalewicka, Deborah M Kurraschorbaugh, David E Nichols


    A conformationally restricted analogue of mescaline, C-(4,5,6-trimethoxyindan-1-yl)-methanamine, was designed using a 5-HT2A Receptor homology model. The compound possessed 3-fold higher affinity and potency than and efficacy equal to that of mescaline at the 5-HT2A Receptor. The new analogue substituted fully for LSD in drug discrimination studies and was 5-fold more potent than mescaline. Resolution of this analogue into its enantiomers corroborated the docking experiments, showing the R-(+) isomer to have higher affinity and potency and to have efficacy similar to that of mescaline at the 5-HT2A Receptor.

  • differential phospholipase c activation by phenylalkylamine serotonin 5 ht2a Receptor agonists
    Journal of Neurochemistry, 2005
    Co-Authors: Jason C Parrish, Michael R Braden, Emily Gundy, David E Nichols


    Experiments compared a series of phenethylamine hallucinogens with their phenylisopropylamine analogues for binding affinity and ability to stimulate serotonin 5-HT2A Receptor-mediated hydrolysis of phosphatidyl inositol in cells expressing cloned rat and human 5-HT2A Receptors. The (±)phenylisopropylamine analogues had significantly higher intrinsic activities for 5-HT2A Receptor-mediated hydrolysis of phosphatidyl inositol compared to their phenethylamine analogues. With respect to the effects of the stereochemistry of the phenylisopropylamines, those with the (R) absolute configuration at the alpha carbon had higher intrinsic activities for hydrolysis of phosphatidyl inositol in a cell line expressing the human 5-HT2A Receptor compared to those with the (S) absolute configuration. In virtual docking studies comparing the (R)- and (S)-phenylisopropylamines with their phenethylamine analogues, there were distinct differences in the orientations of key ligand binding domain residues that have been identified as important by previous mutagenesis studies. In conclusion, our data support the hypothesis that phenylisopropylamines have higher hallucinogenic potency than their phenethylamine analogues primarily because they have higher intrinsic activities at 5-HT2A Receptors. Although virtual ligand binding led to significant perturbations of certain key residues, our results emphasize the conclusion reached by others that overall three-dimensional structural microdomains within the Receptor must be considered.

Kenner C Rice – One of the best experts on this subject based on the ideXlab platform.

  • The 5-HT2A Receptor (5-HT2AR) Regulates Impulsive Action and Cocaine Cue Reactivity in Male Sprague-Dawley Rats.
    Journal of Pharmacology and Experimental Therapeutics, 2018
    Co-Authors: Dennis J Sholler, Sonja J. Stutz, Edward L. Boone, Qin Wang, Kenner C Rice, F. Gerard Moeller, Noelle C. Anastasio, Kathryn A Cunningham


    Impulsivity and the attentional orienting response to cocaine-associated cues (cue reactivity) promote relapse in cocaine-use disorder (CUD). A time-dependent escalation of cue reactivity (incubation) occurs during extended, forced abstinence from cocaine self-administration in rats. The investigational serotonin (5-HT) 5-HT2A Receptor (5-HT2AR) antagonist/inverse agonist M100907 suppresses impulsive action, or the inability to withhold premature responses, and cocaine-seeking behaviors. The present preclinical study was designed to establish the potential for repurposing the Food and Drug Administration-approved selective 5-HT2AR antagonist/inverse agonist pimavanserin as a therapeutic agent to forestall relapse vulnerability in CUD. In male Sprague-Dawley rats, pimavanserin suppressed impulsive action (premature responses) measured in the 1-choice serial reaction time (1-CSRT) task, similarly to M100907. We also used the 1-CSRT task to establish baseline levels of impulsive action before cocaine self-administration and evaluation of cue reactivity (lever presses reinforced by the discrete cue complex previously paired with cocaine delivery). We observed an incubation of cocaine cue reactivity between day 1 and day 30 of forced abstinence from cocaine self-administration. Baseline levels of impulsive action predicted incubated levels of cocaine cue reactivity in late abstinence. We also found that baseline impulsive action predicted the effectiveness of pimavanserin to suppress incubated cue reactivity in late abstinence from cocaine self-administration at doses that were ineffective in early abstinence. These data suggest that integration of clinical measures of impulsive action may inform refined, personalized pharmacotherapeutic intervention for the treatment of relapse vulnerability in CUD.

  • differential effects of serotonin 5 ht1a Receptor agonists on the discriminative stimulus effects of the 5 ht2a Receptor agonist 1 2 5 dimethoxy 4 methylphenyl 2 aminopropane in rats and rhesus monkeys
    Journal of Pharmacology and Experimental Therapeutics, 2010
    Co-Authors: Wouter Koek, Kenner C Rice


    Although many drugs act by indirectly stimulating multiple Receptors (e.g., reuptake inhibitors), relatively little is known about interactions between agonism at different Receptors. This study compared the effect of serotonin (5-HT)1A Receptor agonists with the discriminative stimulus effects of the 5-HT2A Receptor agonist 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) in rats and rhesus monkeys. Eight rats discriminated 0.56 mg/kg i.p. DOM and responded under a fixed ratio (FR) 10 schedule of food presentation, whereas three rhesus monkeys discriminated 0.32 mg/kg s.c. DOM and responded under an FR 5 schedule of stimulus shock termination. DOM and the 5-HT2A Receptor agonists 2,5-dimethoxy-4-n-propylthiophenethylamine (2C-T-7) and dipropyltryptamine (DPT), but not the 5-HT1A Receptor agonists 8-hydroxy-2-(di-n-propylamino) tetralin hydrochloride (8-OH-DPAT) and 3-chloro-4-fluorophenyl-(4-fluoro-4-([(5-methyl-6-methylaminopyridin-2-ylmethyl) amino) methyl] piperidin-1-yl) methanone (F13714), occasioned responding on the DOM-associated lever in rats and monkeys. Both 8-OH-DPAT and F13714 attenuated the discriminative stimulus effects of DOM in monkeys but not in rats; these effects of 8-OH-DPAT and F13714 were prevented by the 5-HT1A Receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide (WAY 100635). DPT and 2C-T-7 enhanced the discriminative stimulus effects of DOM in rats and monkeys in an additive manner. Taken together, the results suggest that the DOM discriminative stimulus is pharmacologically similar and mediated by 5-HT2A Receptors in rats and monkeys; however, the ability of 5-HT1A Receptor agonists to modify the effects of DOM is markedly different between these species. These results indicate possible differences in the neurobiology of 5-HT systems that could be important for studying drugs that have multiple mechanisms of action (e.g., reuptake inhibitors that indirectly stimulate multiple Receptors).

  • role of the serotonin 5 ht2a Receptor in the hyperlocomotive and hyperthermic effects of 3 4 methylenedioxymethamphetamine
    Psychopharmacology, 2005
    Co-Authors: David V Herin, Kenner C Rice, Thomas Ullrich, Kathryn A Cunningham


    Contradictory evidence exists regarding the role of the 5-HT2A Receptor (5-HT2AR) in hyperactivity and hyperthermia elicited by the substituted amphetamine (+)-3,4-methylenedioxymethamphetamine.

Herbert Y Meltzer – One of the best experts on this subject based on the ideXlab platform.

  • direct injection of 5 ht2a Receptor agonists into the medial prefrontal cortex produces a head twitch response in rats
    Journal of Pharmacology and Experimental Therapeutics, 1997
    Co-Authors: David L Willins, Herbert Y Meltzer


    The serotonin (5-HT)2A/2c agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), the 5-HT2C agonist 6-chloro-2-[1-piperazinyl]-pyrazine and the 5-HT2A partial agonist m-chloro-phenylpiperazine (mCPP) were injected bilaterally into the medial prefrontal cortex of male rats. DOI and mCPP, but not 6-chloro-2-[1-piperazinly]-pyrazine, elicited a dose-dependent head-twitch response (HTR). DOI-induced HTR had an ED50 of 12.8 nmoles/0.5 μl/side and was inhibited by the 5-HT2A antagonists ketanserin and MDL 100,907 but was not blocked by pretreatment with the selective 5-HT2C/2B antagonist SDZ SER 082. The HTR to mCPP demonstrated a bell-shaped dose-response curve with an ED50of 1.5 nmoles/0.5 μl/side and a peak effect after 3 nmoles/side. The response to mCPP was greatly diminished by both ketanserin and MDL 100,907 and was partially reversed by SDZ SER 082. These findings suggest that the HTR produced by the direct injection of serotonergic agonists into the medial prefrontal cortex is, in part, mediated by the activation of 5-HT2A Receptors. Pretreatment of rats with the 5-HT1A agonist (±)-8-hydroxy-dipropylaminotetralin hydrobromide inhibited the HTR to DOI. This is consistent with other evidence that suggests a functional antagonism between 5-HT1A and 5-HT2A Receptor activation. The HTR to DOI was potentiated by the novel 5-HT1A selective antagonist WAY 100,635, which suggests that 5-HT1AReceptors tonically regulate this behavioral response to stimulation of cortical 5-HT2A Receptors.