 | |
| Names | |
|---|---|
| IUPAC name (2S)-1-[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]-N-[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pyrrolidine-2-carboxamide | |
| Other names Tyr-Pro-Trp-Phe-NH2;L-Tyrosyl-L-prolyl-L-tryptophyl-L-phenylalaninamide | |
| Identifiers | |
3D model (JSmol) | |
| Abbreviations | YPWF |
| ChEBI | |
| ChEMBL | |
| ChemSpider | |
| |
| |
| Properties | |
| C34H38N6O5 | |
| Molar mass | 610.715 g·mol−1 |
Except where otherwise noted, data are given for materials in theirstandard state (at 25 °C [77 °F], 100 kPa). | |
 | |
| Names | |
|---|---|
| IUPAC name (2S)-1-[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]-N-[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]pyrrolidine-2-carboxamide | |
| Other names Tyr-Pro-Phe-Phe-NH2;L-Tyrosyl-L-prolyl-L-phenylalanyl-L-phenylalaninamide | |
| Identifiers | |
3D model (JSmol) | |
| ChEMBL | |
| ChemSpider | |
| UNII | |
| |
| |
| Properties | |
| C32H37N5O5 | |
| Molar mass | 571.678 g·mol−1 |
Except where otherwise noted, data are given for materials in theirstandard state (at 25 °C [77 °F], 100 kPa). | |
Endomorphins are natural,endogenousopioidneuropeptides that are considered to be central to pain relief.[1] They were first described in 1997 by James Zadina, Abba Kastin and colleagues.[2] The two known endomorphins, endomorphin-1 and endomorphin-2, aretetrapeptides, consisting of Tyr-Pro-Trp-Phe and Tyr-Pro-Phe-Pheamino acid sequences respectively.[3] These sequences fold intotertiary structures with high specificity and affinity for theμ-opioid receptor, binding it exclusively and strongly. Bound μ-opioid receptors typically induce inhibitory effects onneuronal activity.[4] Endomorphin-like immunoreactivity exists within thecentral andperipheral nervous systems, where endomorphin-1 appears to be concentrated in the brain and upperbrainstem, and endomorphin-2 is located mainly in thespinal cord and lower brainstem.[3] Because endomorphins activate the μ-opioid receptor, which is the target receptor ofmorphine and its derivatives, endomorphins possess significant potential asanalgesics with reduced side effects and risk ofaddiction.[5]
Endomorphins belong to the opioid class ofneuropeptides (protein neurotransmitters). Opioids are ligands that bind toopioid receptors[6] and exist both as endogenous substances that are generated within the organism and as synthetic molecules.[1] Endogenous opioids includeendorphins,enkephalins,dynorphins, and endomorphins.[6]
Transcription andtranslation of opioid-encoding genes results in the formation ofpre-propeptide opioid precursors, which are modified in theendoplasmic reticulum to becomepropeptide opioid precursors, transferred to thegolgi apparatus, and further modified into the opioid product.[6] The exact pre-propeptide precursors of endomorphins have not been identified.[5] Because the precursors have never been identified and the mechanisms by which the endomorphins are produced have never been clarified, the status of endomorphins as endogenous opioid ligands has to be considered tentative.
Opioid receptors belong to theG protein-coupled receptor family and include μ, κ, δ, and nociceptinorphanin-FQ receptors.[7] While activation of opioid receptors initiates a diverse array of responses, opioids typically serve asdepressants, and are widely used and developed asanalgesics. Additionally, opioid malfunction has been linked toschizophrenia andautism.[6] Endomorphins demonstrate high selectivity and affinity for the μ-opioid receptor, which functions in pain relief and intoxication.[1]
Both endomorphins-1 and 2 are tetrapeptides, consisting of four amino acids. Endomorphin-1 has the amino acid sequence of Tyr-Pro-Trp-Phe, while endomorphin-2 has a sequence of Tyr-Pro-Phe-Phe.[3] The specific amino acids in these sequences dictate the folding and resultant behavior, namely the ability to bind μ-opioid receptors, of these molecules.
Endomorphins are involved in a variety of functions. Mechanistically, they bind inhibitory μ-opioid G-protein receptors, which act to close calcium ion channels and open potassium ion channels in the membranes of bound neurons.[4] The elimination of calcium influx and facilitation of potassium ion efflux prevents neuronal depolarization, inhibits the generation ofaction potentials, and depresses the activity of excitatory neurons.[4] In other instances, the binding of endomorphins causes excitation, where its activation of phospholipase C and adenylyl cyclase initiates an increase in calcium ion concentration, cellular depolarization, and the release ofnorepinephrine andserotonin.[5]
The specific roles of endomorphins largely remain undetermined and depend upon the pathway in question.[4] Opioid systems influence the physiological processes of pain, reward, and stress. They also play roles in immune responses and the functions of thegastrointestinal,respiratory,cardiovascular, andneuroendocrine systems.[4]
The concentration and resultant effect of most neurotransmitters, including endomorphins, is dictated by rates of synthesis and degradation. Degradation involves the breakdown of functional molecules to defective configurations or parts, thereby reducing the total activity of the molecule type. The enzyme, DPP IV, cleaves endomorphin into defective parts, thus regulating endomorphin activity.[8]
Usingradioimmunoassay andimmunocytochemistry, endomorphins have been localized within the nervous systems of humans, mice, rats, and monkeys.[3] Both endomorphin tetrapeptides are abundant in the humanneocortex.[9] Endomorphin-1 can be found in thehypothalamus andthalamus of thediencephalon, and in thestriatum and lateralseptum of thetelencephalon. In thehindbrain, endomorphin-1-reactive neurons are more abundant than are those immunoreactive for endomorphin-2.[3] Endomorphin-2 is predominantly found in the spinal cord, specifically inpresynaptic terminals ofafferent neurons in the dorsal horn region. It has been found co-localized withcalcitonin and with the pain-conveying neurotransmitter,substance P. Neither endomorphin-1 nor endomorphin-2 has been identified in theamygdala or thehippocampus.[3]
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In addition to endomorphins, morphine and morphine-like opiates target the μ-opioid receptor. Thus, endomorphins have significant potential as analgesics and morphine substitutes.[5]In vitro assessment of endomorphins as analgesics reveals similar behavior to morphine and other opiates, where drug tolerance leads to dependence and addiction. Other side effects common to opiates such asvasodilation,respiratory depression,urinary retention, and gastrointestinal reaction develop.[5] However, the endomorphin-induced side effects are slightly less severe than are those of the morphine-derived analgesics commonly used today. Additionally, endomorphins potentially produce more powerful analgesic effects than their morphine-derived counterparts.[5]
Despite their potential utility as pharmaceutical agents, the low membrane permeability and vulnerability to enzymatic degradation of endomorphins limit their incorporation into drugs. As a result, endomorphin analogues are being generated to allow transport across theblood brain barrier, increase stability, and reduce side effects.[10] Two endomorphin modifications that approach these problems includeglycosylation and lipidation. Glycosylation adds carbohydrate groups to the endomorphin molecules, allowing them to pass membranes via glucose transporters.Lipidation adds lipoamino acids or fatty acids to the endomorphin molecules, increasinghydrophobicity and, therefore, membrane permeability of the molecules.[10]