Definition
A group of opioid peptides has been discovered in the skin of South American frogs belonging to the subfamily Phyllomedusinae. The first peptide isolated from several species of these frogs was dermorphin which was shown to have high affinity and selectivity for µ-type opioid receptors 1.
Related Peptides
After the discovery of dermorphins, two additional peptides with even higher affinity for the d receptor were subsequently isolated from the skin of Phyllomedusa bicolor. Like dermorphin, these peptides contain D-alanine as the second amino acid and they have been termed [D-Ala2] deltorphins I and II 1. Dermorphins and deltorphins are heptapeptides with the common amino terminal sequence Tyr-D-Ala-Phe 2.
Discovery
In 1981, Montecucchi et al., extracted from the skin of the Argentinian frog Phyllomedusa sauvagei a heptapeptide named dermorphin, which preferentially binds to µ-type opioid receptors. Erspamer et al., in 1989 reported the isolation of deltorphins from the skin of P. sauvagei 2.
Structural Characteristics
These are heptapeptides with the common aminoterminal sequence Tyr-D-Ala-Phe. Since this initial sequence is conserved, it is presumed that it is necessary for binding to both µ and d sites of opioid receptors. Unlike dermorphin, the deltorphins have a charged amino acid in position 4, namely histidine in the case of deltorphin and aspartic or glutamic acid in the case of [D-Ala2]-deltorphins. The presence of positively or negatively charged amino acids in this position has little influence on the binding characteristics. It thus seems likely that other features in the C-terminal regions of deltorphins are essential for the observed receptor selectivity. Deltorphins are flexible linear peptides. They show an affinity for d sites 10 to 200 times higher than that of the synthetic enkephalin analogue 2. Deltorphins contain the amino terminal sequence Tyr-Ala-Phe, which is preceded by the typical prohormone processing signal Lys-Arg. Following the deltorphin sequence is the more complex processing sequence Gly-Glu-Ala-Lys-Lys, the glycine being required for the formation of the carboxyl-terminal amide. The same flanking sequences have also been found in the dermorphin precursors from Ph. sauvagei 1.
Analogs: D-Ala2, Glu4] - and [D-Ala2, Asp4] deltorphinamides, their L isomers, and 1-(3, 5-diiodotyrosyl) [D-Ala2] deltorphins are synthetic analogs of deltorphins prepared by solid-phase synthesis 2.
Dermorphin analogs, [Lys7-NH2] dermorphin, [Arg7-NH2] dermorphin, and [Asn7-NH2] dermorphin behave as potent analgesic agents. The antinociception effect of [Lys7-NH2] dermorphin lasts longer than that of dermorphin itself 3.
In another study, the influence of dermorphin analogs with stereochemical modification of the amino acid residue proline in position 6 (Pro6), Tyr-D-Ala-Phe-Gly-Tyr-Hyp-Ser-NH2, Tyr-D-Ala-Phe-Gly-Tyr-[D-Pro]-Ser-NH2, Tyr-D-Ala-Phe-Gly-Tyr-[dehydro-Pro]-Ser-NH2, and Tyr-D-Ala-Phe-Gly-Tyr-[D-dehydro-Pro]-Ser-NH2, was analysed after their intraperitoneal injection at 0.5 mg/kg dose in the cold (4–7°C), thermoneutral (27–28°C), and hot (31–33°C) environment. Stereochemical modifications of amino acid residue Pro6 proved to induce specific changes in the thermoregulatory effect of the peptide. Substitution of DPro6 for Pro6 has the most dramatic consequences: it considerably attenuated the thermoregulatory effect of dermorphin in the cold environment, cancelled it in the hot environment, and inverted the dermorphin-specific thermoregulatory response in thermoneutral conditions. The data thus obtained indicate the important role of Pro6 residue in realization of this physiological activity of dermorphins 4.
Mode of Action
Dermorphin and deltorphins have high affinity and selectivity for µ- and d-type opioid receptors, respectively 2.
Functions
Dermorphin peptides are potent analgesics in rodents and primates, including man. Some dermorphins can enter the blood-brain barrier and produce central antinociception after peripheral administration. The dermorphin family also includes µ 1-opioid receptor selective agonists that produce intense opioid analgesia, but stimulate pulmonary ventilation. Experiments in rats and mice chronically exposed to dermorphins have shown that not only do they have higher antinociceptive efficacy and potency than morphine, but they are also less likely than morphine to produce tolerance, dependence and opiate side effects 5. [3H][D-Ala2] deltorphin I is a valuable probe for binding studies, since its affinity and selectivity are the highest of all the d -selective ligands known to date 2.
References
1. K Richter K, R Egger R, L Negri L, R Corsi R, C Severini C, Kreil G (1990). cDNAs encoding [D-Ala2]deltorphin precursors from skin of Phyllomedusa bicolor also contain genetic information for three dermorphin-related opioid peptides (amphibian skin peptides / precursors). PNAS., 87(12)4836-4839.
2. Erspamer V, Melchiorri P, Falconieri-Erspamer G, Negri L, Corsi R, Severini C, Barra D, Simmaco M Kreil G (1989). Deltorphins: A family of naturally occurring peptides with high affinity and selectivity for d opioid binding sites (amphibian skin peptides/mouse vas deferens assay/receptor binding assay). PNAS., 86:188-5192.
3. Negri L, Erspamer GF, Severini C, Potenza RL, Melchiorri P, Erspamer V (1992). Dermorphin-related peptides from the skin of Phyllomedusa bicolor and their amidated analogs activate two µ opioid receptor subtypes that modulate antinociception and catalepsy in the rat. PNAS., 89:7203-7207.
4. Emel’yanova TG, Usenko AB, Bonartsev AP, Kamenskii AA, Guzevatykh LS, Andreeva LA, Alfeeva L, Myasoedov NF (2002). Effect of Dermorphin Analogs on Thermoregulation of Rats under Various Thermal Conditions. Biology Bulletin, 29(3):284–289.
5. Melchiorri P, Negri L. (1996). The dermorphin peptide family. Gen Pharmacol., 27(7):1099-1107.