Studies of Opioid Peptides

Relaxation times (7)) of carbon nuclei were also applied to the problem. The T, times of the CH backbone were of the same order, a result that implies the same correlation time for the motions of these carbons, including those of the terminal residues. T) data for the Phe4, Leu5, and Tyr1 side-chain carbons indicated that the motion of the Tyr side chain was relatively unrestricted. Similar conclusions were drawn earlier by an American group 152) and from H relaxation time data.(153) Uncertainties in determining the 3J(NH-CH ) values of the Gly residues of the enkephalins have been resolved by a study of specifically deuterated analogs, but the results were considered to provide 

Nmr studies of Phe4 and Tyr1 side-chain conformations have been possible with the aid of deuterated analogs/157 In the case of Tyr1 the conformers 15a and 15b had the higher populations in aqueous solution the former corresponds to the local conformation of the tyramine moiety of crystalline morphine hydrochloride/158  

Finally, reference is made to nmr work on enkephalin analogs with terminal Pro residues that are highly active at /x-receptors (p. 352). Both H 

Energy transfer experiments by spectrofluorimetry enable an estimate to be made of the Tyr-Trp separation in Trp4-Met-enkephalin, an analog that is about a quarter as active as the parent in the MVD test. The value obtained (—10 A) is close to the phenol-phenyl separation in a potent oripavine derivative in support of peptide /3rbend conformations.067  

Quantum mechanical calculations have been applied to opioid peptides in attempts to identify low-energy conformers and to study their relationships to rigid opioids. Of the 52 conformations reported for met-enkephalin,(205) the lowest-energy structures (those with AE = 2.5 kcal/mol) were found to have 

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In the course of less than 10 years the study of opioid peptides has become a discipline in its own right and monographs devoted solely to the topic are now appearing. The monograph on endorphins has already been cited/200 ... 

Spanagel R., Herz A., Shippenberg T. The effects of opioid peptides on dopamine release in the nucleus accumbens an in vivo microdialysis study. J. Neurochem. 55 1734, 1990. 

Ni Q., Xu H., Partilla J. et al. Opioid peptide receptor studies. Interaction of opioid peptides and other drugs with four subtypes of the K2 receptor in guinea pig brain. Peptides. 16 1083, 1995. 

The results of structure-activity studies on opioid peptides revealed that analogues consisting entirely of aromatic amino acids, such as H-Tyr-D-Phe-Phe-NH2 [26] and H-Tyr-D-Phe-Phe-Phe-NH2 [27] were quite potent and selective q-agonists. Systematic replacement of the amino acids in these two peptides... 

Binding of opioids to human MCF-7 breast cancer cells, their effect on growth, as well as the effect of opioid and nicotine receptors on human SCLC have been studied by Maneckzee [98-99]. Kita et al [100] have studied the effect of opioid peptides on the tumoricidal activity of spleen cells with or without tumors. The antimetastatic effect of various enkephalin-like peptides has been studied by Scholar et al [101]. 

Recently, a new class of opioid peptides, the endomorphins (52 and 53, Fig. 7.9), were discovered (264) that do not share the classical "message" sequence with other mammalian opioid peptides. In contrast to other mammalian opioid peptides, the endomorphins show high selectivity for their preferential receptor, the receptor (Table 7.9). Since their discovery the pharmacology of these new mammalian opioid peptides has been studied extensively (see Ref 265 for a detailed review). 

Sdentitic studies of opioid neurotransmitters during the 1970s have uncovered a complex and subtle system that exhibited impressive diversity in terms of endogenous ligands for only three major receptors. The opioid peptide precursors were subject to complex post-translational modifications resulting in the synthesis of multiple active peptides all of them sharing the common N-terminal sequence of Tyr-Gly-Gly-Phe-(Met or Leu), which has been termed the opioid motif. Based on the results of theses studies, the endogenous opioids have been implicated in circuits involved in the control of sensation, emotion, and affect and a role has been ascribed to them in addiction, not only to opiates such as morphine or heroin, but also to alcohol. ... 

R 64 J. Malicka, C. Czaplewski, M. Groth, W. Wiczk, S. Oldziej, L. Lan-kiewicz, J. Ciarkowski and A. Li wo, Use of NMR and Fluorescence Spectroscopy as well as Theoretical Conformational Analysis in Conformation-Activity Studies of Cyclic Enkephalin Analogues , p. 123 R 65 A. Naito and K. Nishimura, Conformational Analysis of Opioid Peptides in the Solid State and the Membrane Environments by NMR Spectroscopy , p. 135... 

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