<i>C</i>-(4,5,6-Trimethoxyindan-1-yl)methanamine:  A Mescaline Analogue Designed Using a Homology Model of the 5-HT<sub>2A</sub> Receptor.

McLean, Thomas H.; Chambers, James J.; Parrish, Jason C.; Braden, M.; Marona‐Lewicka, Danuta; Kurrasch‐Orbaugh, Deborah M.; Nichols, David E.

doi:10.1021/jm0612259

Cited by 6 publications

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“…80,106 In addition, virtual docking studies allowed the design of new agonist ligands as well as the prediction of their more active enantiomers. 104,105 More recently, Isberg et al 79 have developed an in silico-activated model of the 5-HT 2A receptor starting with the published crystal structure of the β-2-adrenergic receptor. Continued refinements of this, and other G protein coupled receptors, will ultimately allow a greater understanding of the molecular features that lead to receptor binding and activation.…”

Section: Receptor Modelsmentioning

confidence: 99%

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Structure–activity relationships of serotonin 5‐HT_2A agonists

Nichols

2012

WIREs Membr Transp Signal

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Of the 14 known types of serotonin receptors one of the most extensively studied is the 5-HT 2A (5-hydroxytryptamine) receptor. In the brain, this receptor plays a key role in regulation of cortical function and cognition, appears to be the principal target for the hallucinogenic/psychedelic drugs such as lysergic acid diethylamide (LSD), and also is a target for the newest atypical antipsychotic agents, which are antagonists or inverse agonists at this site. Among the structure-activity relationships that are known for this receptor type, there are three chemical classes of agonists: tryptamines, ergolines, and phenethylamines. Important structural features are identified for agonist activity and some of these agonists have features in common. In addition to effects at the receptor will be the focus, these drugs are also hallucinogenic (psychedelic) agents, and much of the SAR was developed on the basis of effects in humans, before modern pharmacological techniques were available. A certain amount of our knowledge therefore relies on those human studies.

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Section: Receptor Modelsmentioning

confidence: 99%

“…104 The R enantiomer had an EC50 of 3200 nM for activating IP3 accumulation, whereas the S enantiomer had an EC50 >50,000 nM. The R enantiomer also had efficacy in this pathway virtually identical to mescaline (Figure 27).…”

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confidence: 96%

Structure–activity relationships of serotonin 5‐HT_2A agonists

Nichols

2012

WIREs Membr Transp Signal

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“…ND, not determined. PS, produced only partial substitution for the training drug. a Affinity for [ 125 I]DOI- or [ 3 H]DOB-labeled 5-HT 2A receptors. b McLean et al, 2006a. c Titeler et al, 1988. d Glennon et al, 1992. e McLean et al, 2006b. f Affinity for [ 3 H]ketanserin-labeled 5-HT 2A receptors. g Monte et al, 1997. h Shannon et al, 1984. i Seggel et al, 1990. j Stimulus generalization in rats trained with 1.0 mg/kg DOM HCl (data taken from: Glennon et al, 1983). …”

Section: Highlightsmentioning

confidence: 99%

Role of the 5-HT2A receptor in the locomotor hyperactivity produced by phenylalkylamine hallucinogens in mice

2013

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The 5-HT2A receptor mediates the effects of serotonergic hallucinogens and may play a role in the pathophysiology of certain psychiatric disorders, including schizophrenia. Given these findings, there is a need for animal models to assess the behavioral effects of 5-HT2A receptor activation. Our previous studies demonstrated that the phenylalkylamine hallucinogen and 5-HT2A/2C agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) produces dose-dependent effects on locomotor activity in C57BL/6J mice, increasing activity at low to moderate doses and reducing activity at high doses. DOI did not increase locomotor activity in 5-HT2A knockout mice, indicating the effect is a consequence of 5-HT2A receptor activation. Here, we tested a series of phenylalkylamine hallucinogens in C57BL/6J mice using the Behavioral Pattern Monitor (BPM) to determine whether these compounds increase locomotor activity by activating the 5-HT2A receptor. Low doses of mescaline, 2,5-dimethoxy-4-ethylamphetamine (DOET), 2,5-dimethoxy-4-propylamphetamine (DOPR), 2,4,5-trimethoxyamphetamine (TMA-2), and the conformationally restricted phenethylamine (4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine (TCB-2) increased locomotor activity. By contrast, the non-hallucinogenic phenylalkylamine 2,5-dimethoxy-4-tert-butylamphetamine (DOTB) did not alter locomotor activity at any dose tested (0.1-10 mg/kg i.p.). The selective 5-HT2A antagonist M100907 blocked the locomotor hyperactivity induced by mescaline and TCB-2. Similarly, mescaline and TCB-2 did not increase locomotor activity in 5-HT2A knockout mice. These results confirm that phenylalkylamine hallucinogens increase locomotor activity in mice and demonstrate that this effect is mediated by 5-HT2A receptor activation. Thus, locomotor hyperactivity in mice can be used to assess phenylalkylamines for 5-HT2A agonist activity and hallucinogen-like behavioral effects. These studies provide additional support for the link between 5-HT2A activation and hallucinogenesis.

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“…The reaction was held at reflux for 125 h before cooling and removing the K 2 CO 3 by filtration. After solvent removal in vacuo, the remaining residue was combined with CH 2 Cl 2 , washed with 2.5 M NaOH, 1 M HCl, and brine, and dried over anhydrous MgSO 4 . Evaporation of the volatiles in vacuo yielded an orange solid that was treated with a 10% CH 2 Cl 2 -90% hexanes solution (100 mL) to precipitate the dimeric byproduct.…”

Section: -(2-bromoethoxy)-4-methoxybenzene (8)mentioning

confidence: 99%

“…The aqueous extracts were combined, cooled to 0 °C, and basified by addition of 5M NaOH. The basic solution was extracted with CH 2 Cl 2 , and the organic extract was washed with brine and dried over MgSO 4 . The volatiles were removed in vacuo to yield 17a as a yellow oil.…”

Section: -[(E)-2-nitroethenyl]-3678-tetrahydro-2h-furo-[23-g]chrmentioning

confidence: 99%

‘Hybrid’ benzofuran–benzopyran congeners as rigid analogs of hallucinogenic phenethylamines

Schultz

Prescher

Kidd

et al. 2008

Bioorganic & Medicinal Chemistry

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Phenylalkylamines that possess conformationally rigidified furanyl moieties in place of alkoxy arene ring substituents have been shown previously to possess the highest affinities and agonist functional potencies at the serotonin 5-HT 2A receptor among this chemical class. Further, affinity declines when both furanyl rings are expanded to the larger dipyranyl ring system. The present paper reports the synthesis and pharmacological evaluation of a series of "hybrid" benzofuranyl-benzopyranyl phenylalkylamines to probe further the sizes of the binding pockets within the serotonin 5-HT 2A agonist binding site. Thus, 4(a-b), 5(a-b), and 6 were prepared as homologs of the parent compound, 8-bromo-1-(2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b']difuran-4-yl)-2-aminopropane 2, and their affinity, functional potency, and intrinsic activity were assessed using cells stably expressing the rat 5-HT 2A receptor. The behavioral pharmacology of these new analogs was also evaluated in the twolever drug discrimination paradigm. Although all of the hybrid isomers had similar, nanomolar range receptor affinities, those with the smaller furanyl ring at the arene 2-position (4a-b) displayed a 4-to 15-fold greater functional potency than those with the larger pyranyl ring at that position (5a-b). When the furan ring of the more potent agonist 4b was aromatized to give 6, a receptor affinity similar to the parent difuranyl compound 2 was attained, along with a functional potency equivalent to 2, 4a, and 4b. In drug discrimination experiments using rats trained to discriminate LSD from saline, 4b was more than two times more potent than 5b, the latter having a potency similar to the classic hallucinogenic amphetamine 1 (DOB).

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C-(4,5,6-Trimethoxyindan-1-yl)methanamine: A Mescaline Analogue Designed Using a Homology Model of the 5-HT_2A Receptor.

Cited by 6 publications

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Structure–activity relationships of serotonin 5‐HT_2A agonists

Structure–activity relationships of serotonin 5‐HT_2A agonists

Role of the 5-HT2A receptor in the locomotor hyperactivity produced by phenylalkylamine hallucinogens in mice

‘Hybrid’ benzofuran–benzopyran congeners as rigid analogs of hallucinogenic phenethylamines

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C-(4,5,6-Trimethoxyindan-1-yl)methanamine: A Mescaline Analogue Designed Using a Homology Model of the 5-HT2A Receptor.

Cited by 6 publications

References 0 publications

Structure–activity relationships of serotonin 5‐HT2A agonists

Structure–activity relationships of serotonin 5‐HT2A agonists

Role of the 5-HT2A receptor in the locomotor hyperactivity produced by phenylalkylamine hallucinogens in mice

‘Hybrid’ benzofuran–benzopyran congeners as rigid analogs of hallucinogenic phenethylamines

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C-(4,5,6-Trimethoxyindan-1-yl)methanamine: A Mescaline Analogue Designed Using a Homology Model of the 5-HT_2A Receptor.

Structure–activity relationships of serotonin 5‐HT_2A agonists

Structure–activity relationships of serotonin 5‐HT_2A agonists