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Acta Physiologica 2011; Volume 202, Supplement 684
The Joint Conference (FAMÉ 2011) of the LXXVth Meeting of the Hungarian Physiological Society, XVIth Meeting of the Hungarian Society of Anatomists, Experimental Section of the Hungarian Society for Experimental and Clinical Pharmacology and Hungarian Society for Microcirculation and Vascular Biology
6/8/2011-6/11/2011
Pécs, Hungary
OPIOID AGONIST ACTIVITY OF 14-O-METHOXY-MORPHINE-6-SULFATE AND MORPHINE-6-SULFATE RELATED TO MORPHINE
Abstract number: P50
Lacko1 E., Varadi1 A., Riba1 P., Friedmann1 T., Iemolo1 A., Sobor1 M., Timar1 J., Hosztafi2 S., Noszal2 B., Furst1 S., Al-Khrasani1 M.
Aims:
To analyse in vitro and in vivo opioid properties of the 14-O-methoxy-morphine-6-sulfate (14-O-MeM6S), morphine-6-sulfate (M6S) and morphine.
Methods:
Male NMRI mice (30–45g) and male Wistar rats (160–220g) were used. Vasa deferentia of mouse (MVD, hosting delta, mu and kappa-opioid receptors) and rat (RVD, m-like opioid receptor with low reserve) were used to determine the potency, efficacy and opioid receptor subtype selectivity of the test compounds. Concentration-response curves were cumulatively constructed. Then, the 50% inhibitory effect (IC50), the 50% effective concentration (EC50) and the maximal effect (Emax) were evaluated. The dissociation constant (Ke) values of naloxone (NX) were assessed by single dose method. In vivo, rat tail-flick test (RTF) was performed.
Results:
In MVD, the IC50 and EC50 values indicated that 14-O-MeM6S was potent opioid agonist similarly to DAMGO (D-Ala2,N-Me-Phe4,Gly5-ol-enkephalin), whereas M6S and morphine were weak agonists. The Ke values of NX indicate that tested agents are m-opioid receptor (MOR) selective agonists. The Emax values revealed that 14-O-MeM6S and DAMGO were superior to M6S or morphine in MVD. In addition, in RVD, 14-O-MeM6S and DAMGO but neither M6S nor morphine produced inhibitory effects. In RTF, the analgesic ED50 values (mg/kg) were 0.082 for 14-O-MeM6S, 3.4 for M6S and 2.0 for morphine, when administered subcutaneously (s.c). When injected intracerebroventricularly (i.c.v.), the ED50 values (mg/rat) were 0.062, 0.214 and 12.40 for 14-O-MeM6S, M6S and morphine, respectively. S.c./i.c.v. ratio was 13274 for 14-O-MeM6S, 15836 for M6S and 161 for morphine.
Conclusions:
14-O-MeM6S similarly to DAMGO showed a full agonist character in MVD and RVD whereas M6S and morphine were partial agonists. The higher s.c./i.c.v. ratio for 14-O-MeM6S and M6S may indicate the limited access of the compounds into the brain. Incorporation of methoxy group in C14 of M6S increased the opioid activity and the efficacy of M6S. The remarkable profile of 14-O-MeM6S compared to other tested substances is the full agonist character with higher efficacy.
Support:
OTKA (K-60999) and ETT (374/09)
To cite this abstract, please use the following information:
Acta Physiologica 2011; Volume 202, Supplement 684 :P50