Antinociceptive action of DBO 17 and DBO 11 in mice: two 3,8 diazabicyclo (3.2.1.) octane derivates with selective mu opioid receptor affinity.
Two 3,8 diazabicyclo (3.2.1.) octane derivates, namely DBO 17 and DBO 11, were studied for the opioid-like activity. In the rat brain membrane preparation binding studies, DBO 17 and DBO 11 showed a high affinity and selectivity for the mu opioid receptor (Ki's: 5.1 and 25 nM, respectively). DBO 17 and DBO 11 inhibited the nociceptive response in the hot-plate test of mice with ED50 values of 0.16 mg/kg and 0.44 mg/kg, respectively. The antinociceptive action of both DBO 17 and DBO 11 was blocked by naloxone. Tolerance to the antinociceptive action of DBO 17 and DBO 11 was present after 13 and 7 days of repeated treatment, respectively. Both DBO 17 and DBO 11 were ineffective in morphine-tolerant mice and vice versa. Chronic treatments (three times daily for seven consecutive days) of DBO 17 and DBO 11 induced a naloxone-precipitated withdrawal syndrome in DBO 17 treated mice similar to that in morphine treated mice, whereas in DBO 11 treated mice abstinence signs were virtually absent. These results indicate an interesting pharmacological profile that suggests these compounds as possible new candidates for the clinical treatment of pain.
Fadda
P
P
Dipartimento di Neuroscienze B.B. Brodie Universita' di Cagliari, Italy.
Barlocco
D
D
Tronci
S
S
Cignarella
G
G
Fratta
W
W
D000698:Analgesia; D000700:Analgesics / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001372:Aza Compounds / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D001643:Bridged Bicyclo Compounds / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D004361:Drug Tolerance; D008297:Male; D051379:Mice; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000187:drug effects* / Q000378:metabolism
C110313:3-p-nitrocinnamyl-8-propionyl-3,8-diazabicyclo(3.2.1.)octane; C110314:3-propionyl-8-p-nitrocinnamyl-3,8-diazabicyclo(3.2.1.)octane; D000700:Analgesics; D000701:Analgesics, Opioid; D001372:Aza Compounds; D001643:Bridged Bicyclo Compounds; D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; D009270:Naloxone