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 language | English |
|---|---|
| Pages (from-to) | 2115-2123 |
| Number of pages | 9 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 43 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - Jun 1 2000 |
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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 journal › Article
}
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.
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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 -