Article date: October 1991
By: Sandrine Sagan, A.D. Corbett, M. Amiche, A. Delfour, P. Nicolas, H.W. Kosterlitz, in Volume 104, Issue 2, pages 428-432
To elucidate the structural features required for selective and potent action of dermenkephalin at the δ‐opioid receptor, a series of analogues of dermenkephalin and dermorphin were tested for their effectiveness in depressing electrically‐evoked contractions of the vas deferens of the hamster (δ‐opioid receptors) and the guinea‐pig myenteric plexus‐longitudinal muscle preparation (μ‐ and κ‐opioid receptors).
Dermenkephalin was more selective and more potent at δ‐receptors than the δ‐ligand [d‐Pen2, d‐Pen5]‐enkephalin. The responses to dermenkephalin in the hamster vas deferens were increased by addition of peptidase inhibitors; the maximum effect was obtained with 3 μm thiorphan.
[l‐Met2]‐dermenkephalin had 0.2% and [l‐Ala2]‐dermorphin 0.01% of the agonist activity of the corresponding endogenous peptides which have d‐amino acids in position 2. The pharmacological activity of these analogues was unaffected by inhibition of peptidases. This emphasizes the role that the d‐configuration plays in determining the bioactive folding of these highly active peptides.
Dermenkephalin‐(1–6)‐NH2 was more potent at δ‐receptors than at μ‐receptors whereas, dermenkephalin‐(1–4)‐NH2 is a selective μ‐agonist, having no activity at δ‐receptors.
Substitution of the C‐terminal tripeptide of dermorphin with the C‐terminal tripeptide of dermenkephalin abolished the μ‐receptor preference of dermorphin. The resulting hybrid peptide, Tyr‐d‐Ala‐Phe‐Gly‐Leu‐Met‐Asp‐NH2 was as potent as dermenkephalin at δ‐receptors. A shift towards a preference for δ‐receptors was obtained when the C‐terminal tetrapeptide of dermorphin was replaced by the C‐terminal tetrapeptide of dermenkephalin.
Substitution of Asp by Asn in position 7 of dermenkephalin caused an increase in μ‐receptor potency and a decrease in δ‐receptor potency, resulting in a 20 fold decrease in μ‐receptor selectivity. Dermenkephalin‐(1–6)‐NH2 and [Asn7]‐dermenkephalin have almost identical δ‐receptor agonist potencies and ratios of IC50 in the myenteric plexus to IC50 in the hamster vas deferens.
The results obtained emphasise the importance of a negative charge at the C‐terminus of dermenkephalin for selectivity at the δ‐opioid receptor. Furthermore, the hydrophobic residues Leu5and Met6may be critical in ensuring tight binding to the receptor which results in high agonist potency.
To elucidate the structural features required for selective and potent action of dermenkephalin at the δ‐opioid receptor, a series of analogues of dermenkephalin and dermorphin were tested for their effectiveness in depressing electrically‐evoked contractions of the vas deferens of the hamster (δ‐opioid receptors) and the guinea‐pig myenteric plexus‐longitudinal muscle preparation (μ‐ and κ‐opioid receptors).
Dermenkephalin was more selective and more potent at δ‐receptors than the δ‐ligand [d‐Pen2, d‐Pen5]‐enkephalin. The responses to dermenkephalin in the hamster vas deferens were increased by addition of peptidase inhibitors; the maximum effect was obtained with 3 μm thiorphan.
[l‐Met2]‐dermenkephalin had 0.2% and [l‐Ala2]‐dermorphin 0.01% of the agonist activity of the corresponding endogenous peptides which have d‐amino acids in position 2. The pharmacological activity of these analogues was unaffected by inhibition of peptidases. This emphasizes the role that the d‐configuration plays in determining the bioactive folding of these highly active peptides.
Dermenkephalin‐(1–6)‐NH2 was more potent at δ‐receptors than at μ‐receptors whereas, dermenkephalin‐(1–4)‐NH2 is a selective μ‐agonist, having no activity at δ‐receptors.
Substitution of the C‐terminal tripeptide of dermorphin with the C‐terminal tripeptide of dermenkephalin abolished the μ‐receptor preference of dermorphin. The resulting hybrid peptide, Tyr‐d‐Ala‐Phe‐Gly‐Leu‐Met‐Asp‐NH2 was as potent as dermenkephalin at δ‐receptors. A shift towards a preference for δ‐receptors was obtained when the C‐terminal tetrapeptide of dermorphin was replaced by the C‐terminal tetrapeptide of dermenkephalin.
Substitution of Asp by Asn in position 7 of dermenkephalin caused an increase in μ‐receptor potency and a decrease in δ‐receptor potency, resulting in a 20 fold decrease in μ‐receptor selectivity. Dermenkephalin‐(1–6)‐NH2 and [Asn7]‐dermenkephalin have almost identical δ‐receptor agonist potencies and ratios of IC50 in the myenteric plexus to IC50 in the hamster vas deferens.
The results obtained emphasise the importance of a negative charge at the C‐terminus of dermenkephalin for selectivity at the δ‐opioid receptor. Furthermore, the hydrophobic residues Leu5and Met6may be critical in ensuring tight binding to the receptor which results in high agonist potency.
DOI: 10.1111/j.1476-5381.1991.tb12446.x
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