Synthesis, molecular modeling, and opioid receptor affinity of 9,10- diazatricyclo[4.2.1.12,5]decanes and 2,7- diazatricyclo[4.4.0.03,8]decanes structurally related to 3,8- diazabicyclo[3.2.1]octanes

Paola Vianello, Alberto Albinati, Gerardo A. Pinna, Antonio Lavecchia, Luciana Marinelli, Pier Andrea Borea, Stefania Gessi, Paola Fadda, Silvia Tronci, Giorgio Cignarella

Research output: Contribution to journalArticle

Abstract

Various lines of evidence, including molecular modeling studies, imply that the endoethylenic bridge of 3,8-diazabicyclo[3.2.1]octanes (DBO, 1) plays an essential role in modulating affinity toward μ opioid receptors. This hypothesis, together with the remarkable analgesic properties observed for N3 propionyl, N8 arylpropenyl derivatives (2) and of the reverted isomers (3), has prompted us to insert an additional endoethylenic bridge on the piperazine moiety in order to identify derivatives with increased potency toward this receptor class. In the present report, we describe the synthesis of the novel compounds 9,10-diazatricyclo[4.2.1.12,5]decane (4) and 2,7- diazatricyclo[4.4.0.03,8]decane (5), as well as the representative derivatives functionalized at the two nitrogen atoms by propionyl and arylpropenyl groups (6a-e, 7a-d). Opioid receptor binding assays revealed that, among the compounds tested, the N-propionyl-N-cinnamyl derivatives 6a and 7a exhibited the highest μ-receptor affinity, and remarkably, compound 7a displayed in vivo (mice) an analgesic potency 6-fold that of morphine.

Original languageEnglish
Pages (from-to)2115-2123
Number of pages9
JournalJournal of Medicinal Chemistry
Volume43
Issue number11
DOIs
Publication statusPublished - Jun 1 2000

Fingerprint

Octanes
Molecular modeling
Opioid Receptors
Analgesics
Derivatives
Morphine
Nitrogen
Isomers
Assays
Atoms
decane

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Synthesis, molecular modeling, and opioid receptor affinity of 9,10- diazatricyclo[4.2.1.12,5]decanes and 2,7- diazatricyclo[4.4.0.03,8]decanes structurally related to 3,8- diazabicyclo[3.2.1]octanes. / Vianello, Paola; Albinati, Alberto; Pinna, Gerardo A.; Lavecchia, Antonio; Marinelli, Luciana; Borea, Pier Andrea; Gessi, Stefania; Fadda, Paola; Tronci, Silvia; Cignarella, Giorgio.

In: Journal of Medicinal Chemistry, Vol. 43, No. 11, 01.06.2000, p. 2115-2123.

Research output: Contribution to journalArticle

Vianello, Paola ; Albinati, Alberto ; Pinna, Gerardo A. ; Lavecchia, Antonio ; Marinelli, Luciana ; Borea, Pier Andrea ; Gessi, Stefania ; Fadda, Paola ; Tronci, Silvia ; Cignarella, Giorgio. / Synthesis, molecular modeling, and opioid receptor affinity of 9,10- diazatricyclo[4.2.1.12,5]decanes and 2,7- diazatricyclo[4.4.0.03,8]decanes structurally related to 3,8- diazabicyclo[3.2.1]octanes. In: Journal of Medicinal Chemistry. 2000 ; Vol. 43, No. 11. pp. 2115-2123.
@article{9d1887d48a8c49afbd6b48fa8936d98e,
title = "Synthesis, molecular modeling, and opioid receptor affinity of 9,10- diazatricyclo[4.2.1.12,5]decanes and 2,7- diazatricyclo[4.4.0.03,8]decanes structurally related to 3,8- diazabicyclo[3.2.1]octanes",
abstract = "Various lines of evidence, including molecular modeling studies, imply that the endoethylenic bridge of 3,8-diazabicyclo[3.2.1]octanes (DBO, 1) plays an essential role in modulating affinity toward μ opioid receptors. This hypothesis, together with the remarkable analgesic properties observed for N3 propionyl, N8 arylpropenyl derivatives (2) and of the reverted isomers (3), has prompted us to insert an additional endoethylenic bridge on the piperazine moiety in order to identify derivatives with increased potency toward this receptor class. In the present report, we describe the synthesis of the novel compounds 9,10-diazatricyclo[4.2.1.12,5]decane (4) and 2,7- diazatricyclo[4.4.0.03,8]decane (5), as well as the representative derivatives functionalized at the two nitrogen atoms by propionyl and arylpropenyl groups (6a-e, 7a-d). Opioid receptor binding assays revealed that, among the compounds tested, the N-propionyl-N-cinnamyl derivatives 6a and 7a exhibited the highest μ-receptor affinity, and remarkably, compound 7a displayed in vivo (mice) an analgesic potency 6-fold that of morphine.",
author = "Paola Vianello and Alberto Albinati and Pinna, {Gerardo A.} and Antonio Lavecchia and Luciana Marinelli and Borea, {Pier Andrea} and Stefania Gessi and Paola Fadda and Silvia Tronci and Giorgio Cignarella",
year = "2000",
month = "6",
day = "1",
doi = "10.1021/jm991140q",
language = "English",
volume = "43",
pages = "2115--2123",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "11",

}

TY - JOUR

T1 - Synthesis, molecular modeling, and opioid receptor affinity of 9,10- diazatricyclo[4.2.1.12,5]decanes and 2,7- diazatricyclo[4.4.0.03,8]decanes structurally related to 3,8- diazabicyclo[3.2.1]octanes

AU - Vianello, Paola

AU - Albinati, Alberto

AU - Pinna, Gerardo A.

AU - Lavecchia, Antonio

AU - Marinelli, Luciana

AU - Borea, Pier Andrea

AU - Gessi, Stefania

AU - Fadda, Paola

AU - Tronci, Silvia

AU - Cignarella, Giorgio

PY - 2000/6/1

Y1 - 2000/6/1

N2 - Various lines of evidence, including molecular modeling studies, imply that the endoethylenic bridge of 3,8-diazabicyclo[3.2.1]octanes (DBO, 1) plays an essential role in modulating affinity toward μ opioid receptors. This hypothesis, together with the remarkable analgesic properties observed for N3 propionyl, N8 arylpropenyl derivatives (2) and of the reverted isomers (3), has prompted us to insert an additional endoethylenic bridge on the piperazine moiety in order to identify derivatives with increased potency toward this receptor class. In the present report, we describe the synthesis of the novel compounds 9,10-diazatricyclo[4.2.1.12,5]decane (4) and 2,7- diazatricyclo[4.4.0.03,8]decane (5), as well as the representative derivatives functionalized at the two nitrogen atoms by propionyl and arylpropenyl groups (6a-e, 7a-d). Opioid receptor binding assays revealed that, among the compounds tested, the N-propionyl-N-cinnamyl derivatives 6a and 7a exhibited the highest μ-receptor affinity, and remarkably, compound 7a displayed in vivo (mice) an analgesic potency 6-fold that of morphine.

AB - Various lines of evidence, including molecular modeling studies, imply that the endoethylenic bridge of 3,8-diazabicyclo[3.2.1]octanes (DBO, 1) plays an essential role in modulating affinity toward μ opioid receptors. This hypothesis, together with the remarkable analgesic properties observed for N3 propionyl, N8 arylpropenyl derivatives (2) and of the reverted isomers (3), has prompted us to insert an additional endoethylenic bridge on the piperazine moiety in order to identify derivatives with increased potency toward this receptor class. In the present report, we describe the synthesis of the novel compounds 9,10-diazatricyclo[4.2.1.12,5]decane (4) and 2,7- diazatricyclo[4.4.0.03,8]decane (5), as well as the representative derivatives functionalized at the two nitrogen atoms by propionyl and arylpropenyl groups (6a-e, 7a-d). Opioid receptor binding assays revealed that, among the compounds tested, the N-propionyl-N-cinnamyl derivatives 6a and 7a exhibited the highest μ-receptor affinity, and remarkably, compound 7a displayed in vivo (mice) an analgesic potency 6-fold that of morphine.

UR - http://www.scopus.com/inward/record.url?scp=0034214133&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034214133&partnerID=8YFLogxK

U2 - 10.1021/jm991140q

DO - 10.1021/jm991140q

M3 - Article

C2 - 10841790

AN - SCOPUS:0034214133

VL - 43

SP - 2115

EP - 2123

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 11

ER -