Pinna, Gérard Aimé and Cignarella, Giorgio and Loriga, Giovanni and Murineddu, Gabriele and Mussinu, Jean-Mario and Stefania, Ruiu and Fadda, Paola and Walter, Fratta (2002) N-3(9)-arylpropenyl-N-9(3)-propionyl-3,9-diazabicyclo[3.3.1]nonanes as µ-opioid receptor agonists. Effects on µ-affinity of arylalkenyl chain modifications. Bioorganic & Medicinal Chemistry, Vol. 10 (6), p. 1929-1937. ISSN 0968-0896. Article.
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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 µ-, δ- and k-receptors were evaluated. Several compounds (1e,i,j-2d,e,f,g,j) exhibited a µ-affinity in the low nanomolar range with moderate or negligible affinity towards δ- and k-receptors. The representative term N-9-(3,3-diphenylprop-2-enyl)-N-3-propionyl-DBN (2d) displayed in vivo (mouse) a potent analgesic effect (ED50 3.88 mg/kg ip) which favourably compared with that of morphine (ED50 5 mg/kg ip). In addition, 2d produced in mice tolerance after a period twice as long with morphine.
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