Enkephalin tyrosine

The 2-nitrile derivative 191 was exploited subsequently 118) to give a methionine enkephalin analog with either (-)- or (+)-metazocine in place of the enkephalin tyrosine unit, by standard chemistry (Scheme 4.19). Each compound was, at best, weakly antinociceptive. 

Fluorescence anisotropy decay of [Leu ] enkephalin tyrosine was measured using the frequency- domain up to 10 GHz. The data indicate a 44 ps cori elation time for local tyrosine motions and a 219 ps correlation time for overall rotational diffusion of the pentapeptide (Lakowicz et al. 1993). Also a rotational correlation time of 26 ps was measured by H NMR for Ha of tyrosine in position 1 of L-dermorphin (Simenel, 1990). These ps values determined by NMR and by fluorescence spectroscopy are the result of possible significant atomic fluctuations that occur in the picosecond time scale (Karplus and Me Gammon, 1981). Since it was difficult in quenching experiments performed on DREK to measure such short correlation times we do not know whether these atomic fluctuations would depend on the conformation of the peptide or not. However, our results clearly put into evidence the presence of a local rotation within DREK. 

In the solid, dynamics occurring within the kHz frequency scale can be examined by line-shape analysis of 2H or 13C (or 15N) NMR spectra by respective quadrupolar and CSA interactions, isotropic peaks16,59-62 or dipolar couplings based on dipolar chemical shift correlation experiments.63-65 In the former, tyrosine or phenylalanine dynamics of Leu-enkephalin are examined at frequencies of 103-104 Hz by 2H NMR of deuterated samples and at 1.3 x 102 Hz by 13C CPMAS, respectively.60-62 In the latter, dipolar interactions between the 1H-1H and 1H-13C (or 3H-15N) pairs are determined by a 2D-MAS SLF technique such as wide-line separation (WISE)63 and dipolar chemical shift separation (DIP-SHIFT)64,65 or Lee-Goldburg CP (LGCP) NMR,66 respectively. In the WISE experiment, the XH wide-line spectrum of the blend polymers consists of a rather featureless superposition of components with different dipolar widths which can be separated in the second frequency dimension and related to structural units according to their 13C chemical shifts.63... 

There are also several reports of Li+-induced effects upon the endorphins (see ref. 162). More recently it has been shown that Li+ also enhances the activity of tyrosine aminopeptidase in rat pituitary gland [167]. This could result in changes in the levels of the enkephalins which are primarily degraded by aminopeptidases via cleavage of the tyrosine-glycine amide bond [168]. 

There are several biologically important peptides which contain tyrosine but not tryptophan. These include small molecules with molecular weights of about 1000 or less. Molecules such as oxytocin, vasopressin, and tyrocidine A are cyclic, while others such as angiotensin II and enkephalin are linear. Schiller 19) has reviewed the literature up through 1984 on fluorescence of these and several other peptides. One major finding that has been reported recently is that the anisotropy and fluorescence intensity decays of many peptides are complex. This is especially evident in some of the tyrosine-containing peptides, and we expect that there will be considerable effort made over the next few years toward understanding the physical basis for these complex kinetics. 

The mobility of tyrosine in Leu3 enkephalin was examined by Lakowicz and Maliwal/17 ) who used oxygen quenching to measure lifetime-resolved steady-state anisotropies of a series of tyrosine-containing peptides. They measured a phase lifetime of 1.4 ns (30-MHz modulation frequency) without quenching, and they obtained apparent rotational correlation times of 0.18 ns and 0.33 ns, for Tyr1 and the peptide. Their data analysis assumed a simple model in which the decays of the anisotropy due to the overall motion of the peptide and the independent motion of the aromatic residue are single exponentials and these motions are independent of each other. 

Lakowicz et al.(]7] VB) examined the intensity and anisotropy decays of the tyrosine fluorescence of oxytocin at pH 7 and 25 °C. They found that the fluorescence decay was best fit by a triple exponential having time constants of 80, 359, and 927 ps with respective amplitudes of 0.29, 0.27, and 0.43. It is difficult to compare these results with those of Ross et al,(68) because of the differences in pH (3 vs. 7) and temperature (5° vs. 25 °C). For example, whereas at pH 3 the amino terminus of oxytocin is fully protonated, at pH 7 it is partially ionized, and since the tyrosine is adjacent to the amino terminal residue, the state of ionization could affect the tyrosine emission. The anisotropy decay at 25 °C was well fit by a double exponential with rotational correlation times of 454 and 29 ps. Following the assumptions described previously for the anisotropy decay of enkephalin, the longer correlation time was ascribed to the overall rotational motion of oxytocin, and the shorter correlation time was ascribed to torsional motion of the tyrosine side chain. 

Faraj et al. [28] studied the effects of different concentrations of leucine enkephalin, peptidase inhibitors, and sodium glycocholate (GC) on the stability and absorption of leucine enkephalin in nasal cavities of rats. Based on the study, the rate and extent of formation of des-tyrosine leucine enkephalin... 

The three-dimensional disposition of the nitrogen function to the aromatic ring allows morphine and other analgesics to bind to a pain-reducing receptor in the brain. The terminal tyrosine residue in the natural agonists Met-enkephalin and Leu-enkephalin is mimicked by portions of the morphine structure. 

Figure 1. Flat of C-13 chemical shift of C-/3 of tyrosine in enkephalin as a function of pH meter reading in D O, 30° C...

The present study has shown that enkephalin binds to PS in a pH-dependent fashion. The binding most likely involves the NHa group of the tyrosine residue of enkephalin and the CO2 group of PS. We have measured for the interaction and find it to be of the order of 5 x 10 M ("pH" 6.3) which is much weaker than the interaction of PS with morphine derivatives. Upon binding of enkephalin to PS the correlation time for internal motion in the backbone of the peptide increases by at least one order of magnitude (from 7.0 x 10" sec rad" ). The Ti of the bound peptide... 

The main objective of this experiment was to demonstrate that a peptide lead compound could be used in rational design of a non-peptide library. One of the natural opiates, met-enkephalin, is used as a hypothetical lead compound. The averaged frequency distribution based on four SA runs is obtained (data not shown). Based on this result, 03 had the highest frequency, and the frequencies of A4, Dll, D13, D14, D16, D2, D3, D5, and D9 are also above random expectation. Apparently, 03 appeared in all the reported active peptoids with opioid activity (cf. Table 1). Comparison of the structure of met-enkephalin (Fig. 5) with 03 indicated that 03 is similar to the side chain of tyrosine, which is the N-terminal residue of met-enkephalin. Among other building blocks found more frequently than random expectation, A4, D3, and D13 are present in the reported opioid peptoids (cf. Table 1). Thus, the SA sampling correctly identified four... 

After the early discovery of a tyrosine 0-sulfate residue in bovine fibrinopeptide B, 15 this posttranslational modification which occurs ubiquitously in proteins was also detected in a series of biologically active peptides such as the neurohormones of the gastrin/cholecysto-kinin (CCK) family of peptides, phyllokinin, Leu-enkephalin, and the thrombin inhibitor hirudin listed in Table 1. 

Scsack, Susan R., and Virginia M. Picket. 1992. "Dual Ultrastructural Localization of Enkephalin and Tyrosine Hydroxylase Immunoreactivity in the Rat Ventral Tegmental Area Multiple Substrates for Opiate-Dopamine Interactions." Journal of Neuroscience 12 1335-50. 

Met-enkephalin is just one of many endorphins, which are pain-relieving polypeptides produced by the body. Studies show a similarity between the structure of opioids and the structure of the tyrosine—glycine-glycine portion of this macromolecule, a similarity that supports the notion that endorphins and opioids fit the same receptor sites. 

Figure 9. Experimental static maps in the plane of the tyrosine (a) and of the phenylalanine residue, (b) in leu-enkephalin. Contours as in Figure 6.

Aminopeptidases are involved in the metabolism of opioid peptides including enkephalins and /3-endorphins. An HPLC method was developed to measure the hydrolysis of these compounds by measuring the formation of tyrosylglycyl-glycine, tyrosylglycine, and tyrosine. 

Enkephalinase A (dipeptidyl carboxypeptidase) and enkephalinase B (dipep-tidyl aminopeptidase) are involved in the degradation of enkephalin, which has an opiate-like activity. Enkephalinase A cleaves methionine enkephalin (Tyr-Gly-Gly-Phe-Met) after the second glycine, whereas enkephalinase B cleaves after the first glycine. A postcolumn derivatization system is used to detect N-terminal tyrosine-containing peptides. 

In the 1970s, Hughes et al. were the first to show that two very different chemical structures have similar agonist properties (3). The opioid natural product, morphine (3), was found to resemble the N-terminal structure of the endogenous opioid peptides, enkephalins, (4a) and (4b), and j3-endorphin (5) (Fig. 15.2). The remarkable similarity between the morphine phenol system and the IV-terminal tyrosine residue in the peptide opioids implied that these units reacted with opioid receptors in a similar fashion to elicit comparable responses (4-6). 

The pentapeptides, met- and leu-enkephalin, have been detected in rat striatum tissue by LCEC at a glassy carbon electrode. These peptides can be detected directly because they contain an electroactive tyrosine residue. A series of endorphins, also containing tyrosine, have been detected by LCEC. ... 

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