Cyclic analogues of Tyr-W-MIF-1 with prolonged analgesic activity and potency comparable to DAMGO and morphine.
ABSTRACT Two cyclic analogues of the brain peptide Tyr-W-MIF-1 (Tyr-Pro-Trp-Gly-NH2) were synthesized and tested for analgesic activity in the rat tail flick test after intracerebroventricular (ICV) injection. The analogues were about 200-fold more potent than the parent peptide. Analgesia was dose dependent, and at 1 microgram the two analogues, the mu-selective enkephalin analogue DAMGO (Tyr-D-Ala-Gly-N-Me-Phe-Gly-ol), and morphine, all produced analgesia lasting between 40 and 60 min. Analgesia of longer duration was evident at higher doses of the analogues and lasted more than 6 h after 100 micrograms, the highest dose tested. The results show that peptide analogues based on the structure of the endogenously occurring Tyr-W-MIF-1 can produce potent and long-lasting effects on nociception.
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Article: Opioid receptors and ligands.[Show abstract] [Hide abstract]
ABSTRACT: This review gives a historical perspective, summarizing approximately 25 years of research on opioids. The "typical" opioid peptides produced in the brain, "atypical" opioids encrypted in milk protein or hemoglobin sequences, and extremely potent and selective opioids of amphibian origin are described. The main focus is on the structure-activity relationship studies of peptide ligands for three main opioid receptor types (μ, δ, κ), their selectivities and pharmacological activities in vitro . Chemical modifications that led to obtaining potent and selective agonists and antagonists for these receptors are discussed. Opioid peptides and their multiple receptors are part of the neurohormonal system. Endogenous opioid peptides are small molecules that are naturally produced in the central nervous system (CNS) and in various glands throughout the body, such as the pituitary and adrenal glands. These peptides produce the same effects as the chemicals known as classic alkaloid opiates, which include morphine and heroine. Endogenous opioid peptides function both as hormones and as neuromodulators. Endogenous opioid peptides that serve as hormones are secreted into the circulation by the producing glands and are delivered to a variety of distant target tissues, where they induce a response. Endogenous opioid peptides that serve as neuromodulators are produced and secreted by nerve cells and act in the brain and spinal cord to modulate the actions of other neurotransmitters. Through these two mechanisms, endogenous opioid peptides produce a large spectrum of physiological effects, ranging from inducing pain relief to preventing diarrhea. The development of the synthetic opioid receptor-specific ligands, both peptide and non-peptide, is of great importance. If they can provide a description of the particular physiological characteristics of each receptor type it should be possible to design new drugs that may produce only selected physiological responses. The development of potent opioid agonists and antagonists with high specificity for each of the three main receptor classes continues to be of major concern in opioid pharmacology. This review summarizes two decades of research on endogenous opioid system, in particular on the three main types of opioid receptors and their ligands. Structure-activity relationship studies of peptide agonist and antagonist analogs of endogenous and synthetic ligands that have biological activity and therapeutic potential are discussed. This articleNIDA research monograph 02/1989; 95:159-66.
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ABSTRACT: Spinal administration of morphine or [D-Ala2,MePhe4,Gly(ol)5)]enkephalin (DAMGO) produces potent, naloxone-reversible analgesia that is modulated by alpha 2-adrenoceptors. Tyr-W-MIF-1 (Tyr-Pro-Trp-Gly-NH2) is a naturally occurring, amidated tetrapeptide that is structurally related to the melanocyte-stimulating hormone release inhibiting factor-1 (MIF-1) family of endogenous peptides. Tyr-W-MIF-1 displays high selectivity for the mu-opioid receptor. We investigated the effect of spinal administration of Tyr-W-MIF-1 on analgesia using the mouse tail-flick assay. Intrathecal (i.t.) administration of Tyr-W-MIF-1 produced a dose-dependent analgesic response, with an ED50 of 0.41 microgram, that was reversed by naloxone. Pretreatment with the mu-opioid receptor-selective antagonist beta-funaltrexamine blocked the effect of i.t. Tyr-W-MIF-1. However, pretreatment with the mu1-opioid receptor-selective antagonist naloxonazine did not antagonize the analgesia, indicating the effect was mediated through spinal mu2-opioid receptors. Pretreatment with desipramine, an inhibitor of norepinephrine reuptake, potentiated the analgesic effect of i.t. Tyr-W-MIF-1, producing a 3.1-fold leftward shift in the dose-response curve. Spinal administration of yohimbine, an alpha 2-adrenoceptor-selective antagonist, significantly attenuated the analgesic effect of Tyr-W-MIF-1. Thus, the potent analgesic effect of i.t. Tyr-W-MIF-1 is mediated through spinal mu2-receptors, and is modulated by norepinephrine and alpha 2-adrenoceptors.European Journal of Pharmacology 04/1996; 298(3):235-9. DOI:10.1016/0014-2999(95)00823-3 · 2.68 Impact Factor
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ABSTRACT: Two endogenous brain peptides (Tyr-W-MIF-1 (Tyr-Pro-Trp-Gly-NH2) and Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2)), a cyclized analog and two fragments of Tyr-W-MIF-1, and hemorphin (Tyr-Pro-Trp-Thr) were tested for binding to mu 1 and mu 2 opiate receptor. All these peptides bound to both mu 1 and mu 2 sites in assays optimized to discriminate these subtypes of the mu opiate receptor in membranes from bovine thalamus. The cyclized analog of Tyr-W-MIF-1, previously shown to have potency near that of Tyr-D-Ala-Gly-N-MePhe-Gly-ol (DAMGO) and morphine in producing analgesia after intracerebroventricular (i.c.v.) injection, bound to mu 1 and mu 2 sites with affinities similar to those of DAMGO. Tyr-W-MIF-1, previously shown to induce analgesia after i.c.v. injection but with much higher potency after intrathecal (i.t.) injection, also bound to both mu 1 and mu 2 sites with an affinity between that of morphiceptin and hemorphin. Although the highest ratios of Ki's for mu 2/mu 1 were shown by hemorphin, Tyr-W-MIF-1, and Tyr-W-MIF-1, none of the compounds were significantly different in selectivity. The results indicate that the relatively lower potency of Tyr-W-MIF-1 after i.c.v., compared with i.t. injection, is not due to a lack of binding to mu 1 sites. They suggest that it has relatively high efficacy at mu 2, but low efficacy at mu 1 sites, a possibility that might explain some of the novel properties of these peptides.Neuroscience Letters 09/1996; 215(1):65-9. DOI:10.1016/S0304-3940(96)12928-1 · 2.06 Impact Factor