N-3(9)-arylpropenyl-N-9(3)-propionyl-3,9-diazabicyclo[3.3.1]nonanes as mu-opioid receptor agonists. Effects on mu-affinity of arylalkenyl chain modifications.
Two series of N-3-arylpropenyl-N-9-propionyl-3,9-diazabicyclo[3.3.1]nonanes (1b-j) and of the reverted N-3-propionyl-N-9-arylpropenyl isomers (2b-j) as analogues of the previously reported analgesic N-3(9)-cinnamyl-N-9(3)-propionyl-3,9-diazabicyclo[3.3.1]nonanes (DBN) (1a, 2a) were synthesised and their affinity and selectivity towards opioid mu-, delta- and kappa-receptors were evaluated. Several compounds (1e,i,j-2d,e,f,g,j) exhibited a mu-affinity in the low nanomolar range with moderate or negligible affinity towards delta- and kappa-receptors. The representative term N-9-(3,3-diphenylprop-2-enyl)-N-3-propionyl-DBN (2d) displayed in vivo (mouse) a potent analgesic effect (ED(50) 3.88 mg/kg ip) which favourably compared with that of morphine (ED(50) 5 mg/kg ip). In addition, 2d produced in mice tolerance after a period twice as long with morphine.
Pinna
Gérard A
GA
Dipartimento Farmaco Chimico Tossicologico, Università di Sassari, via F. Muroni 23/A, 07100, Sassari, Italy. pinger@uniss.it
Cignarella
Giorgio
G
Loriga
Giovanni
G
Murineddu
Gabriele
G
Mussinu
Jean Mario
JM
Ruiu
Stefania
S
Fadda
Paola
P
Fratta
Walter
W
D000701:Analgesics, Opioid / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000166:cytology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D015394:Molecular Structure; D010147:Pain Measurement; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D000701:Analgesics, Opioid; D019086:Bridged Bicyclo Compounds, Heterocyclic; D017450:Receptors, Opioid, mu