Synthesis, molecular modeling, and opioid receptor affinity of 9, 10-diazatricyclo[4.2.1.1(2,5)]decanes and 2,7-diazatricyclo[4.4.0. 0(3,8)]decanes structurally related to 3,8-diazabicyclo[3.2. 1]octanes.
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 mu opioid receptors. This hypothesis, together with the remarkable analgesic properties observed for N(3) propionyl, N(8) 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. 1.1(2,5)]decane (4) and 2,7-diazatricyclo[4.4.0.0(3,8)]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 mu-receptor affinity, and remarkably, compound 7a displayed in vivo (mice) an analgesic potency 6-fold that of morphine.
Vianello
P
P
Istituto di Chimica Farmaceutica e Tossicologica, Viale Abruzzi 42, 20131 Milano, Italy.
Albinati
A
A
Pinna
G A
GA
Lavecchia
A
A
Marinelli
L
L
Borea
P A
PA
Gessi
S
S
Fadda
P
P
Tronci
S
S
Cignarella
G
G
D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D001667:Binding, Competitive; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008958:Models, Molecular; D051381:Rats; D011957:Receptors, Opioid / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000700:Analgesics; D001372:Aza Compounds; D011957:Receptors, Opioid