5-Agonist Leus enkephalin

Fig. 1. Structures of two types of opioid agonists where dotted circles surround structural elements common to both compounds (a) Leu-enkephalin and...

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. 

Endogenous opioid peptides. Extensive processing is also involved in formation of analgesic opioid peptides, which are present naturally in the brain (see also Section B). Tire formation of (1-endorphin in the hypothalamus from prepro-opiomelanocortin (Fig. 30-2) has already been mentioned. Prior to the discovery of P-endorphin, the pentapeptides Met-enkephalin and Leu-enkephalin (Table 30-4) were discovered and were found to compete with opiate drugs for receptors in the brain. Tire larger P-endorphin, which contains the Met-enkephalin sequence at its N terminus, is a far more potent opiate antagonist than are the enkephalins. Since the Met-enkephalin sequence within P-endorphin is not flanked by basic residues, it apparently is normally not released. Two other recently discovered brain peptides are endomorphin-1 (YPWF-NH2) and endomorphin-2 (YPFF-NH2). They are also potent agonists for the opioid receptors, especially the p receptor (see Section B,10).,61a,61b... 

Leu-Enkephalin (= YGGFL)] (hexapeptide) Endogenous animal opiate O-R agonist [analgesic, narcotic]... 

The potency of [d-Ala2]Leu-enkephalin in GPI and MVD assays is differentially altered when L-Leu is replaced by the D-amino acid, [D-Ala2-D-Leus]enkephalin (DADL) is half as effective as the parent in the ileum test but three times more active in the MVD procedure (see data)(57) DADL is now commonly employed as a selective 5-agonist (see p 356) Thus,... 

Fig 10 1 The agonist activities of various compounds in the mouse vas deferens and guinea pig ileum and their potencies to inhibit 3H-Leu-enkephalm and [3H]naloxone binding in homogenates of guinea pig brain (pH 7 4 at 0°C, no Na+, 150 min) The numbers on the absiccsa indicate the amino acid sequence of /3 -lipoprotein, Leu, leu-enkephalin and Mo, morphine All peptides are synthetic (61-91, ovine /3-endorphin, 61-65, met-enkephahn and leu-enkephalin)... 

Both peptides behave as agonists and inhibit opiate receptor binding, with affinities comparable to the affinity of morphine. The effects of met-enkephalin and leu-enkephalin are reversed by naloxone. Three distinct families of peptides... 

The actions listed for antagonists are seen with the antagonist alone. All the correlations in this table are based on studies in rats and mice, which occasionally show species differences. Thus, any extensions of these associations to humans are tentative. Clinical studies do indicate that (x receptors elicit analgesia spinally and supraspinally. Preliminary work with a synthetic opioid peptide, [D-Ala, D-Leu ]enkephalin, suggests that intrathecal 8 agonists are analgesic in humans. 

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