Quasi-atomistic Receptor Surrogates for the 5-HT2A Receptor: A 3D-QSAR Study on Hallucinogenic Substances

Schulze-Alexandru, Meike; Kovar, Karl‐Artur; Vedani, Angelo

doi:10.1002/(sici)1521-3838(199912)18:6<548::aid-qsar548>3.3.co;2-2

Cited by 4 publications

(8 citation statements)

References 6 publications

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“…Another seven ligands select a single conformer with a preference >90 %, 10 with a preference >50 %, while the remaining three ligands (S23, S21, S31) calculate their mean interaction signi®cantly from more than one conformer. In the 3D-QSAR study [1], only 10 of the 30 conformers were identi®ed``correctly'' (cf. Table 3)Ðsuggesting an error rate of 67 % in selecting the bioactive conformer.…”

Section: Resultsmentioning

confidence: 97%

“…Relative energies of the various ligand conformers were determined by full minimization using the AMBER force ®eld and implicit aqueous solvent. A training set comprising 23 molecules (92 conformers total) representing the largest possible diversity from the whole data set was then de®ned following [1]. The remaining seven ligands (28 conformers total) served as the test set.…”

Section: Resultsmentioning

confidence: 99%

“…How do the results from 4D-QSAR compare with our earlier study based on 3D-QSAR [1]? This can be best discussed by analyzing the selected conformers.…”

Section: Resultsmentioning

confidence: 99%

“…Values given in italics represent the 3D-QSAR study [1]. The most frequently selected fraction is shown in bold face Ligand nth cf; E(rel) Fraction #1 nth cf; E(rel) Fraction #2 nth cf; E(rel) Fraction #3 nth cf; E(rel) Fraction #4 nth cf; E(rel) Fraction 3D cross-over cycles [51], rather than after 8,000 in the 3D-approach [1]. This cross validated r 2 of the scramble textÐan criterion for the sensitivity of the model towards the biological dataÐis a more critical parameter.…”

Section: Resultsmentioning

confidence: 99%

“…It yielded a cross-validated r 2 of 0.954 and a predictive r 2 of 0.860. Subsequently, a series of 53 hypothetical congeneric compounds was evaluated with some of the ligands showing a predicted activity close to the experimental value of LSD [1]. Inherent with the 3D-QSAR approach, each agonist molecule was represented by a single conformation derived from a conformational search.…”

Section: Introductionmentioning

confidence: 99%

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Induced Fit—The Key for Understanding LSD Activity? A 4D-QSAR Study on the 5-HT2A Receptor System

Streich¹,

Neuburger-Zehnder²,

Vedani³

2000

Quant. Struct.-Act. Relat.

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Using a 4D-QSAR approach (software Quasar) allowing for multiple-conformation, orientation and protonation-state ligand representation as well as for the simulation of induced-®t phenomena, we have validated a family of receptor surrogates for the 5-HT 2A receptor system. The evolution was based on a population of 200 receptor models and simulated during 6,000 cross-over steps, corresponding to 30 generations. It yielded a cross-validated r 2 of 0.951 for the 23 ligands of the training set and a predictive r 2 of 0.859 for the 7 ligands of the test set. In this simulation, all ligand molecules were represented by four different conformers, obtained from a Monte-Carlo search in implicit aqueous solution. A series of six scramble tests (with an average predictive r 2 of À1.05) indicate a high sensitivity of the surrogate family towards the biological data.The quantitative analysis of the contribution of the individual functional groups to the free energy of ligand binding, DG , reveals that the key factors for strong bindingÐand hence activityÐare the ligand desolvation energy and the costs associated with induced ®t, the adaptation of the receptor-binding site to the ligand topology. While the ammonium functionality is essential for recognition, its contribution to DG is not favorable due to a high desolvation energy; important groups are rather methoxy and halide substituents. For most ligand molecules, the evolution does not select the lowest-energy conformer, contrary to previous assumptions in a corresponding 3D-QSAR study.

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Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

“…How do the results from 4D-QSAR compare with our earlier study based on 3D-QSAR [1]? This can be best discussed by analyzing the selected conformers.…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Induced Fit—The Key for Understanding LSD Activity? A 4D-QSAR Study on the 5-HT2A Receptor System

Streich¹,

Neuburger-Zehnder²,

Vedani³

2000

Quant. Struct.-Act. Relat.

Self Cite

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3D-QSAR study of hallucinogenic phenylalkylamines by using CoMFA approach

Zhang

et al. 2007

J Comput Aided Mol Des

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The three-dimensional quantitative structure-activity relationship (3D-QSAR) has been studied on 90 hallucinogenic phenylalkylamines by the comparative molecular field analysis (CoMFA). Two conformations were compared during the modeling. Conformation I referred to the amino group close to ring position 6 and conformation II related to the amino group trans to the phenyl ring. Satisfactory results were obtained by using both conformations. There were still differences between the two models. The model based on conformation I got better statistical results than the one about conformation II. And this may suggest that conformation I be preponderant when the hallucinogenic phenylalkylamines interact with the receptor. To further confirm the predictive capability of the CoMFA model, 18 compounds with conformation I were randomly selected as a test set and the remaining ones as training set. The best CoMFA model based on the training set had a cross-validation coefficient q (2) of 0.549 at five components and non cross-validation coefficient R (2) of 0.835, the standard error of estimation was 0.219. The model showed good predictive ability in the external test with a coefficient R (pre) (2) of 0.611. The CoMFA coefficient contour maps suggested that both steric and electrostatic interactions play an important role. The contributions from the steric and electrostatic fields were 0.450 and 0.550, respectively.

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Binding and functional structure-activity similarities of 4-substituted 2,5-dimethoxyphenyl isopropylamine analogues at 5-HT2A and 5-HT2B serotonin receptors

et al. 2023

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Certain 4-substituted analogs of 1-(2,5-dimethoxyphenyl)isopropylamine (2,5-DMA) are psychoactive classical hallucinogens or serotonergic psychedelic agents that function as human 5-HT2A (h5-HT2A) serotonin receptor agonists. Activation of a related receptor population, h5-HT2B receptors, has been demonstrated to result in adverse effects including cardiac valvulopathy. We previously published on the binding of several such agents at the two receptor subtypes. We hypothesized that, due to their structural similarity, the 5-HT2A and 5-HT2B receptor affinities of these agents might be related, and that QSAR studies might aid future studies. For a series of 13 compounds, it is demonstrated here that i) their published rat brain 5-HT2 receptor affinities are significantly correlated with their h5-HT2A (r = 0.942) and h5-HT2B (r = 0.916) affinities, ii) as with r5-HT2 receptor affinity, h5-HT2A affinity is correlated with the lipophilicity of the 4-position substituent (r = 0.798), iii) that eight of the ten compounds examined in functional (Ca+2 mobilization in stable cell lines generated expressing the human 5-HT2B receptor using the Flp-In T-REx system) assays acted as h5-HT2B agonists (4-substituent = H, F, Br, I, OCH2CH3, NO2, nC3H7, tC4H9) and two (n-hexyl and benzyl) as antagonists, iv) h5-HT2B affinity but not action was correlated with the lipophilicity of the 4-position substituent (r = 0.750; n = 10). The findings suggest that h5-HT2B receptor affinity, and its relationship to substituent lipophilicity, might be approximated by rat and h5-HT2A affinity but cannot be used as a predictor of h5-HT2B agonist action of 2,5-DMA analogs. Furthermore, given that certain 2,5-DMA analogs are on the clandestine market, their potential to produce cardiac side effects following persistent or chronic use via activation of h5-HT2B receptors should be considered.

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Quasi-atomistic Receptor Surrogates for the 5-HT2A Receptor: A 3D-QSAR Study on Hallucinogenic Substances

Cited by 4 publications

References 6 publications

Induced Fit—The Key for Understanding LSD Activity? A 4D-QSAR Study on the 5-HT2A Receptor System

Induced Fit—The Key for Understanding LSD Activity? A 4D-QSAR Study on the 5-HT2A Receptor System

3D-QSAR study of hallucinogenic phenylalkylamines by using CoMFA approach

Binding and functional structure-activity similarities of 4-substituted 2,5-dimethoxyphenyl isopropylamine analogues at 5-HT2A and 5-HT2B serotonin receptors

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