NEUROPEPTIDES--MOLECULAR MECHANISM OF ACTION

项目确定的物理化学和生物活性性质

Project determined the physicochemical and bioactivity properties of opioid peptides: 1. Opioidmimetic dipeptides containing /Dmt/ and /Tic/ with extremely high d affinity (Ki = 0.02 nM) and selectivity (Kim/Kid = 150,000); tripeptides, containing L-Ala3, with /Kim/Kid = 20,000/. Tyr-Tic cognates weakly interacted with d receptors. Observations: (i) peptides are antagonists; (ii) smallest peptides to elicit highly potent opioid properties; (iii) free acid at C-terminus repulses binding from m receptor sites; (iv) L-isomer critical, since D-Tic decreased d binding and in combination with amide produced m selective peptides; and (v) none interacted with k receptors. Physiological data revealed that peptides were antagonists, reversing the antinociceptive activity of deltorphin icv or systemically suggesting passage through the blood rain barrier. Statistical analyses indicated that H-Dmt-Tic-OH fits one-site binding models, whereas H-Dmt-Tic-ol and the tripeptides fit two-site binding models. 2. Opioid infidelity:novel opioid peptide agonists with dual high affinity for d and m receptors. 3. Design and synthesis of deltorphin analogues modified at positions 2-4 with achiral Ca,a-dialkyl cyclic a-amino acids. Results: (I) D-isomer at position 2 not essential for high selectivity, high affinity; (ii) acid function not required for high affinity, but only for d selectivity.