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Abstract
When a dimeric ligand can react bivalently, one would expect an increase in affinity, selectivity, and possibly biological activity. On this premise, we have synthesized and characterized two series of dimers, viz.: Dimeric Pentapeptide Enkephalin (DPEn = (H-Tyr-D-Ala-Gly-Phe-Leu-NH-)2 · (CH2)n, and Dimeric Tetrapeptide Enkephalin (DTEn) = (H-Tyr-D-Ala-Gly-Phe-NH)2 · (CH2)n, with n = 2, 4, …, 12. These dimers display affinity, activity, and δ/μ selectivity which vary systematically with chain length (n). DPE2 shows a seven-fold increase in affinity for the δ receptor of whole brain and NG108-15 cells, relative to monomer, while its activity for the μ receptor is similar to enkephalin monomers. DTE12 shows a dramatic increase in δ selectivity relative to its monomer. The association rate constant for 3H-DPE2 is increased two-fold and its dissociation rate constant is significantly reduced, relative to monomer. DPE2 shows a loss of affinity in the presence of Na+ or Mn++, while GTP unexpectedly increases its affinity under some conditions. DPE2 shows equal potency with the agonist [D-Ala2, D-Leu5] enkephalin in assays measuring their inhibitory effect on prostaglandin E1-stimulated cAMP production by NG108-15 cells. DPE2 is very potent in the mouse vas deferens assay; DTE12 shows substantially less activity. These results suggest that δ opiate receptors may be closely clustered in the cell membrane, and provide new approaches to the development of δ and μ receptor ligands.