Membrane-assisted receptor subtype selection: synthesis, membrane structure, and opioid receptor affinity of [Phe8,12]- and [Phe8,12, Lys10]dynorphin-(1–13)-tridecapeptide
✍ Scribed by Kiichiro Nakajima; Daniel Erne; John W. Bean; David F. Sargent; Robert Schwyzer; Stewart J. Paterson; Hans W. Kosterlitz
- Book ID
- 104203723
- Publisher
- Elsevier Science
- Year
- 1988
- Tongue
- French
- Weight
- 943 KB
- Volume
- 44
- Category
- Article
- ISSN
- 0040-4020
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✦ Synopsis
Two analogs of dynorphin A-(1-13)~tridecapeptide (1) were prepared by conventional synthesis in solution with Isolation and characterization of intermediates. In [Phe8'12, Lys"]dynorphin A-(1-13)-tridecapeptide (2). the helix-breaking residue Pro-10 was replaced by Lys-10, and Ile-8 and Leu-12 were replaced by Phe. In [Phe8"2]dynorphin A-(l-13)-tridecapeptide (a), Pro-10 was retained. Analog 2 was expected, and shown by CD and IR, to assume an a-helical structure in 2,2.2-trifluoroethanol that was longer than the helices of 1 and 3. In contact with a hydrophilic-hydrophobic interface or on a lipid membrane, 2 and & were predicted to insert their N-termini into the more hydrophobic phase as perpendicularly oriented a-helical nonapeptide domains, residues lo-13 remaining in the aqueous phase as random coils. The results of IR-ATR studies with 2 on flat, macroscopic, l-palmitoyl-2-oleoyl-sn_glycero-3-phosphatidylcholine membranes confirmed the predicted structure, which is also typical of 1. The hydrophobic dissociation constant estimated for the interaction of 2 with an aqueous-hydrophobic interface (2.9 x 10-6 M) was consistent with the binding data obtained by capacitance minimization for the binding of 2 to dioleoylphosphatidylcholine membranes. The strong affinity of 2 and & for opioid K-receptors in guinea-pig brain homogenates agreed with the postulated membrane structures and affinities. However, 2 was bound more strongly to opioid &-receptors than 1 and &. A tentative explanation of the enhanced &selection was based on similarities of 2 with B-endorphin. tropln-(l-24)-tetracosapeptlde,2 substance P,3 bombesin.4 and neuromedin B 4 insert their N-or C-terminal message segments Into the hydrophobic membrane compartments as perpendicularly oriented, o-helical domains. Other peptldes of the oplold, melanocortln, neurokinln, and neuromedin families are elther indifferent towards the membrane, or suffer attraction or repulsion by electrostatic Interactions. Such membrane structures and membrane accumulations can be estlmated with reasonable accuracy from the properties of the Individual amlno acid residues.5 Helix length, hydrophobic and electrostatic assoclatlon, and orlentation are calculated from the free energy of transfer, from the net charge, and from the molecular amphiphilic and helix dipole moments.