Receptor constants for endomorphin-1 and endomorphin-1-ol indicate differences in efficacy and receptor occupancy

• Published in: European journal of pharmacology Vol. 421; no. 1; pp. 61 - 67
• Main Authors: Al-Khrasani, Mahmoud, Orosz, György, Kocsis, László, Farkas, Viktor, Magyar, Anna, Lengyel, Imre, Benyhe, Sándor, Borsodi, Anna, Rónai, András Z
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 01.06.2001; Elsevier
• Subjects: Analgesics, Opioid - pharmacology; Animals; Binding, Competitive - drug effects; Biological and medical sciences; Cell receptors; Cell structures and functions; DAMGA (( d-Ala 2, MePhe 4, Gly 5-NH 2)-enkephalin); DAMGO (( d-Ala 2, MePhe 4, Gly 5-ol)-enkephalin); Dose-Response Relationship, Drug; Endomorphin-1-ol; Endomorphin-2-ol; Enkephalin, Ala-MePhe-Gly- - metabolism; Enkephalin, Ala-MePhe-Gly- - pharmacology; Fundamental and applied biological sciences. Psychology; Guinea Pigs; guinea-pig; Ileum; In Vitro Techniques; Male; Mice; Molecular and cellular biology; mouse; Neuropeptide receptors; Oligopeptides - chemistry; Oligopeptides - metabolism; Oligopeptides - pharmacology; Receptor constant; Receptors, Opioid, mu - agonists; Receptors, Opioid, mu - metabolism; Vas deferens; Vas Deferens - drug effects; Vas Deferens - metabolism; β-Funaltrexamine; Endomorphin-2-ol; β-Funaltrexamine; Endomorphin-1-ol; DAMGO (( d-Ala 2, MePhe 4, Gly 5-ol)-enkephalin); Ileum; Receptor constant; DAMGA (( d-Ala 2, MePhe 4, Gly 5-NH 2)-enkephalin); Vas deferens; Agonist; Digestive system; Opioid receptor; Rodentia; Gut; μ Opioid receptor; Smooth muscle; Urinary tract; β-Endorphin; In vitro; C terminal-Sequence; Vertebrata; Biological fixation; Mammalia; Guinea pig; Longitudinal muscle; Structure activity relation; Mouse; Animal
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(01)01014-7

The opioid properties of endomorphin derivatives containing a C-terminal alcoholic(-ol) function were compared to the parent amidated compounds in isolated organs (longitudinal muscle strip of guinea-pig ileum and mouse vas deferens). Similar data were also generated for the μ-opioid receptor selective agonist synthetic peptide ( d-Ala 2, MePhe 4, Gly 5-ol)-enkephalin (DAMGO) and its Gly 5-NH 2 congener (DAMGA). Endomorphin-1-ol (Tyr-Pro-Trp-Phe-ol) had an IC 50 of 80.6 nM in mouse vas deferens and 61.2 nM in guinea-pig ileum; the corresponding values for endomorphin-2-ol (Tyr-Pro-Phe-Phe-ol) were 49.6 and 48.2 nM, for DAMGO 59.8 and 29.2 nM, respectively. As it was indicated by the antagonism by naltrexone, the agonist actions were exerted exclusively at μ-opioid receptors in both organs. The -ol derivatives were slightly (2.3–4.3 times) less potent than the parent amides in the bioassays: all peptides had, apparently, full agonist properties in intact preparations. With the aim of revealing potential partial agonist properties among the investigated peptides, we partially inactivated the μ-opioid receptor pool in mouse vas deferens by 5×10 −7 M β-funaltrexamine. The calculated receptor constants indicated a “high-affinity, low intrinsic efficacy” profile (i.e. a potential partial agonist property) for endomorphin-1, an intermediate character for endomorpin-1-ol and full agonism for DAMGA and DAMGO. Apparently, a higher receptor fraction remained accessible for endomorphin-1 (42.8%) than for the -ol congener (14.0%), DAMGO (20.2%) and DAMGA (14.1%) after partial inactivation.