Favourable involvement of α 2A-adrenoreceptor antagonism in the I 2-imidazoline binding sites-mediated morphine analgesia enhancement

Valerio Mammoli; Alessandro Bonifazi; Fabio Del Bello; Eleonora Diamanti; Mario Giannella; Alan L. Hudson; Laura Mattioli; Marina Perfumi; Alessandro Piergentili; Wilma Quaglia; Federica Titomanlio; Maria Pigini

doi:10.1016/j.bmc.2012.02.016

Favourable involvement of α _2A-adrenoreceptor antagonism in the I ₂-imidazoline binding sites-mediated morphine analgesia enhancement

Valerio Mammoli
, Alessandro Bonifazi
, Fabio Del Bello
, Eleonora Diamanti
, Mario Giannella
, Alan L. Hudson
, Laura Mattioli
, Marina Perfumi
, Alessandro Piergentili
, Wilma Quaglia
, Federica Titomanlio
, Maria Pigini

Research output: Contribution to journal › Article › peer-review

45 Scopus citations

Abstract

Aim of the present study was to obtain novel α ₂- adrenoreceptor (α ₂-AR) antagonists, possibly endowed with subtype-selectivity. Therefore, inspired by the non subtype-selective α ₂-AR antagonist idazoxan, we designed 1,4-dioxane derivatives bearing an aromatic area in position 5 or 6 and the imidazoline nucleus in position 2. Among the novel molecules 1-6, compound 2, with a trans stereochemical relationship between 5-phenyl and 2-imidazoline groups, was able to antagonize the sole α _2A-subtype. Moreover, 2 showed an affinity at I ₂-imidazoline binding sites (I ₂-IBS) comparable to that at α _2A-AR. In in vivo studies 2 strongly increased morphine analgesia. This interesting behaviour appeared to be induced by the favourable involvement of α _2A-AR antagonism in the I ₂-IBS-mediated morphine analgesia enhancement.

Original language	English (US)
Pages (from-to)	2259-2265
Number of pages	7
Journal	Bioorganic and Medicinal Chemistry
Volume	20
Issue number	7
DOIs	https://doi.org/10.1016/j.bmc.2012.02.016
State	Published - Apr 1 2012
Externally published	Yes

Keywords

1,4-Dioxane nucleus
I -IBS morphine analgesia modulation
Morphine analgesia enhancement
α -Adrenoreceptor antagonists

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

Access to Document

10.1016/j.bmc.2012.02.016

Cite this

Mammoli, V., Bonifazi, A., Del Bello, F., Diamanti, E., Giannella, M., Hudson, A. L., Mattioli, L., Perfumi, M., Piergentili, A., Quaglia, W., Titomanlio, F., & Pigini, M. (2012). Favourable involvement of α _2A-adrenoreceptor antagonism in the I ₂-imidazoline binding sites-mediated morphine analgesia enhancement. Bioorganic and Medicinal Chemistry, 20(7), 2259-2265. https://doi.org/10.1016/j.bmc.2012.02.016

Mammoli, V, Bonifazi, A, Del Bello, F, Diamanti, E, Giannella, M, Hudson, AL, Mattioli, L, Perfumi, M, Piergentili, A, Quaglia, W, Titomanlio, F & Pigini, M 2012, 'Favourable involvement of α _2A-adrenoreceptor antagonism in the I ₂-imidazoline binding sites-mediated morphine analgesia enhancement', Bioorganic and Medicinal Chemistry, vol. 20, no. 7, pp. 2259-2265. https://doi.org/10.1016/j.bmc.2012.02.016

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title = "Favourable involvement of α 2A-adrenoreceptor antagonism in the I 2-imidazoline binding sites-mediated morphine analgesia enhancement",

abstract = "Aim of the present study was to obtain novel α 2- adrenoreceptor (α 2-AR) antagonists, possibly endowed with subtype-selectivity. Therefore, inspired by the non subtype-selective α 2-AR antagonist idazoxan, we designed 1,4-dioxane derivatives bearing an aromatic area in position 5 or 6 and the imidazoline nucleus in position 2. Among the novel molecules 1-6, compound 2, with a trans stereochemical relationship between 5-phenyl and 2-imidazoline groups, was able to antagonize the sole α 2A-subtype. Moreover, 2 showed an affinity at I 2-imidazoline binding sites (I 2-IBS) comparable to that at α 2A-AR. In in vivo studies 2 strongly increased morphine analgesia. This interesting behaviour appeared to be induced by the favourable involvement of α 2A-AR antagonism in the I 2-IBS-mediated morphine analgesia enhancement.",

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AU - Giannella, Mario

AU - Hudson, Alan L.

AU - Mattioli, Laura

AU - Perfumi, Marina

AU - Piergentili, Alessandro

AU - Quaglia, Wilma

AU - Titomanlio, Federica

AU - Pigini, Maria

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AB - Aim of the present study was to obtain novel α 2- adrenoreceptor (α 2-AR) antagonists, possibly endowed with subtype-selectivity. Therefore, inspired by the non subtype-selective α 2-AR antagonist idazoxan, we designed 1,4-dioxane derivatives bearing an aromatic area in position 5 or 6 and the imidazoline nucleus in position 2. Among the novel molecules 1-6, compound 2, with a trans stereochemical relationship between 5-phenyl and 2-imidazoline groups, was able to antagonize the sole α 2A-subtype. Moreover, 2 showed an affinity at I 2-imidazoline binding sites (I 2-IBS) comparable to that at α 2A-AR. In in vivo studies 2 strongly increased morphine analgesia. This interesting behaviour appeared to be induced by the favourable involvement of α 2A-AR antagonism in the I 2-IBS-mediated morphine analgesia enhancement.

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