Simultaneous activation of two different receptor systems by enkephalin/neurotensin conjugates having spacer chains of various lengths.
Bivalent ligands composed of enkephalin and neurotensin were prepared and their action in the receptor-receptor interaction was studied with the neuroblastoma cell, NG108-15. Enkephalin was connected via oligosarcosine spacer chain to the N-terminus of neurotensin(8-13). The bivalent ligand stimulated the cGMP production more than plain neurotensin. The affinity of the bivalent ligands for the neurotensin receptor changed with varying lengths of the spacer chain. When the spacer chain was an octamer or a dodecamer of sarcosine, the receptor affinity of those bivalent ligands was higher than neurotensin(1-13), and significantly decreased in the presence of excess amount of enkephalin. These results suggest that the bivalent ligands bind to opioid receptor and neurotensin receptor simultaneously, leading to receptor-receptor interaction. On the other hand, some bivalent ligands, especially that without a spacer chain seemed to bind to the neurotensin receptor by the help of the enkephalin part interacting with a receptor exosite.
Yano
K
K
Department of Polymer Chemistry, Kyoto University, Yoshida Honmachi, Sakyo-ku, Kyoto 606-01, Japan.
Kimura
S
S
Imanishi
Y
Y
D000818:Animals; D002417:Cattle; D002942:Circular Dichroism; D006152:Cyclic GMP / Q000378:metabolism; D004745:Enkephalins / Q000378:metabolism / Q000494:pharmacology*; D009447:Neuroblastoma / Q000378:metabolism; D009496:Neurotensin / Q000378:metabolism / Q000494:pharmacology*; D011487:Protein Conformation; D018028:Receptors, Neurotensin / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D011957:Receptors, Opioid / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D004745:Enkephalins; D018028:Receptors, Neurotensin; D011957:Receptors, Opioid; D011993:Recombinant Fusion Proteins; D009496:Neurotensin; D006152:Cyclic GMP