Synthesis of 3,6-diazabicyclo[3.1.1]heptanes as novel ligands for the opioid receptors

Giovanni Loriga; Ilaria Manca; Gabriele Murineddu; Giorgio Chelucci; Stefania Villa; Stefania Gessi; Lucio Toma; Giorgio Cignarella; Gerard A. Pinna

doi:10.1016/j.bmc.2005.09.045

Synthesis of 3,6-diazabicyclo[3.1.1]heptanes as novel ligands for the opioid receptors

Giovanni Loriga, Ilaria Manca, Gabriele Murineddu, Giorgio Chelucci, Stefania Villa, Stefania Gessi, Lucio Toma, Giorgio Cignarella, Gerard A. Pinna

Fondazione IRCCS Ca' Granda- Ospedale Maggiore Policlinico

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

Abstract

In an effort to improve diazabicycloalkane-based opioid receptor ligands, N-3(6)-arylpropenyl-N-6(3)-propionyl-3,6-diazabicyclo[3.1.1]heptanes (3A,Ba-i) were synthesized and their affinity and selectivity towards μ-, δ- and κ-receptors were evaluated. The results of the current study revealed a number of compounds (3Bb, 3Bg and 3Bh) having a high affinity for μ (K _i at μ-receptors ranging from 2.7 to 7.9 nM) versus δ (K_i at δ-receptors >2000 nM) and versus κ (K _i at κ-receptors >5000 nM) receptors. Molecular modelling carried out on the pair 3Aa/3Ba and on the 3Bh was consistent with the hypothesis that the two series of compounds 3A and 3B interact with the μ-receptor in very different ways.

Original language	English
Pages (from-to)	676-691
Number of pages	16
Journal	Bioorganic and Medicinal Chemistry
Volume	14
Issue number	3
DOIs	https://doi.org/10.1016/j.bmc.2005.09.045
Publication status	Published - Feb 1 2006

Keywords

Molecular modelling
Opioid receptors affinities and selectivities
Synthesis of 3,6-diazabicyclo[3.1.1]heptanes

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Organic Chemistry
Drug Discovery
Pharmaceutical Science

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10.1016/j.bmc.2005.09.045

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Synthesis of 3,6-diazabicyclo[3.1.1]heptanes as novel ligands for the opioid receptors. / Loriga, Giovanni; Manca, Ilaria; Murineddu, Gabriele; Chelucci, Giorgio; Villa, Stefania; Gessi, Stefania; Toma, Lucio; Cignarella, Giorgio; Pinna, Gerard A.

In: Bioorganic and Medicinal Chemistry, Vol. 14, No. 3, 01.02.2006, p. 676-691.

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

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title = "Synthesis of 3,6-diazabicyclo[3.1.1]heptanes as novel ligands for the opioid receptors",

abstract = "In an effort to improve diazabicycloalkane-based opioid receptor ligands, N-3(6)-arylpropenyl-N-6(3)-propionyl-3,6-diazabicyclo[3.1.1]heptanes (3A,Ba-i) were synthesized and their affinity and selectivity towards μ-, δ- and κ-receptors were evaluated. The results of the current study revealed a number of compounds (3Bb, 3Bg and 3Bh) having a high affinity for μ (K i at μ-receptors ranging from 2.7 to 7.9 nM) versus δ (Ki at δ-receptors >2000 nM) and versus κ (K i at κ-receptors >5000 nM) receptors. Molecular modelling carried out on the pair 3Aa/3Ba and on the 3Bh was consistent with the hypothesis that the two series of compounds 3A and 3B interact with the μ-receptor in very different ways.",

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AU - Loriga, Giovanni

AU - Manca, Ilaria

AU - Murineddu, Gabriele

AU - Chelucci, Giorgio

AU - Villa, Stefania

AU - Gessi, Stefania

AU - Toma, Lucio

AU - Cignarella, Giorgio

AU - Pinna, Gerard A.

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AB - In an effort to improve diazabicycloalkane-based opioid receptor ligands, N-3(6)-arylpropenyl-N-6(3)-propionyl-3,6-diazabicyclo[3.1.1]heptanes (3A,Ba-i) were synthesized and their affinity and selectivity towards μ-, δ- and κ-receptors were evaluated. The results of the current study revealed a number of compounds (3Bb, 3Bg and 3Bh) having a high affinity for μ (K i at μ-receptors ranging from 2.7 to 7.9 nM) versus δ (Ki at δ-receptors >2000 nM) and versus κ (K i at κ-receptors >5000 nM) receptors. Molecular modelling carried out on the pair 3Aa/3Ba and on the 3Bh was consistent with the hypothesis that the two series of compounds 3A and 3B interact with the μ-receptor in very different ways.

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Synthesis of 3,6-diazabicyclo[3.1.1]heptanes as novel ligands for the opioid receptors

Abstract

Keywords

ASJC Scopus subject areas

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