The C-terminal residues Met6 and Asp7 of dermenkephalin are the key to its exceptional delta-receptor selectivity — overriding the mu-preference of its N-terminal opioid core.
Two residues determine selectivityMet6 and Asp7 override the mu-preferring opioid core to achieve delta selectivity
What the researchers found
The C-terminal residues Met6 and Asp7 of dermenkephalin are the primary determinants of delta-opioid receptor selectivity, overriding the mu-preferring N-terminal domain.
Why it matters
This work identified the molecular rules for making peptides selective for delta-opioid receptors. Delta receptors may produce pain relief with fewer side effects than mu receptors.
How the study worked
Structure-activity analysis using synthetic analogs, deletions, and hybrid peptides. Binding affinity at mu and delta sites was measured in brain membrane preparations.
What this study cannot tell us
In-vitro binding study. Receptor selectivity in binding assays may not perfectly predict selectivity in functional or in-vivo settings.
How to read the evidence
Preliminary in-vitro study with systematic structure-activity analysis — excellent mechanistic insight.
When this study was published
Published in 1989 — elucidated the molecular basis of natural receptor selectivity.
The bigger picture
Modular peptide design — where an active core is tuned by accessory residues — is a powerful strategy for drug development. This natural example guides rational design of receptor-selective therapeutics.
Questions still open
- Can the selectivity-determining tail be grafted onto other opioid peptides?
- Could similar modular design apply to non-opioid peptide drugs?
Common questions
What is receptor selectivity?
Why is delta-selectivity useful?
Read the original research
Molecular determinants of receptor affinity and selectivity of the natural delta-opioid agonist, dermenkephalin.
The Journal of biological chemistry, 264(29), 17100-6
Citation
Sagan, S; Amiche, M; Delfour, A; Mor, A; Camus, A; Nicolas, P. (1989). Molecular determinants of receptor affinity and selectivity of the natural delta-opioid agonist, dermenkephalin.. The Journal of biological chemistry, 264(29), 17100-6.