Endomorphin

Last updated
Endomorphin-1
Endomorphin 1.svg
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)
AbbreviationsYPWF
ChEBI
ChEMBL
ChemSpider
PubChem CID
  • InChI=1S/C34H38N6O5/c35-26(17-22-12-14-24(41)15-13-22)34(45)40-16-6-11-30(40)33(44)39-29(19-23-20-37-27-10-5-4-9-25(23)27)32(43)38-28(31(36)42)18-21-7-2-1-3-8-21/h1-5,7-10,12-15,20,26,28-30,37,41H,6,11,16-19,35H2,(H2,36,42)(H,38,43)(H,39,44)/t26-,28-,29-,30-/m0/s1
    Key: ZEXLJFNSKAHNFH-SYKYGTKKSA-N
  • C1C[C@H](N(C1)C(=O)[C@H](CC2=CC=C(C=C2)O)N)C(=O)N[C@@H](CC3=CNC4=CC=CC=C43)C(=O)N[C@@H](CC5=CC=CC=C5)C(=O)N
Properties
C34H38N6O5
Molar mass 610.715 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Endomorphin-2
Endomorphin 2.svg
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
PubChem CID
UNII
  • InChI=1S/C32H37N5O5/c33-25(18-23-13-15-24(38)16-14-23)32(42)37-17-7-12-28(37)31(41)36-27(20-22-10-5-2-6-11-22)30(40)35-26(29(34)39)19-21-8-3-1-4-9-21/h1-6,8-11,13-16,25-28,38H,7,12,17-20,33H2,(H2,34,39)(H,35,40)(H,36,41)/t25-,26-,27-,28-/m0/s1
    Key: XIJHWXXXIMEHKW-LJWNLINESA-N
  • C1C[C@H](N(C1)C(=O)[C@H](CC2=CC=C(C=C2)O)N)C(=O)N[C@@H](CC3=CC=CC=C3)C(=O)N[C@@H](CC4=CC=CC=C4)C(=O)N
Properties
C32H37N5O5
Molar mass 571.678 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Endomorphins are considered to be natural opioid neuropeptides central to pain relief. [1] The two known endomorphins, endomorphin-1 and endomorphin-2, are tetrapeptides, consisting of Tyr-Pro-Trp-Phe and Tyr-Pro-Phe-Phe amino acid sequences respectively. [2] These sequences fold into tertiary structures with high specificity and affinity for the μ-opioid receptor, binding it exclusively and strongly. Bound μ-opioid receptors typically induce inhibitory effects on neuronal activity. [3] Endomorphin-like immunoreactivity exists within the central and peripheral nervous systems, where endomorphin-1 appears to be concentrated in the brain and upper brainstem, and endomorphin-2 in the spinal cord and lower brainstem. [2] Because endomorphins activate the μ-opioid receptor, which is the target receptor of morphine and its derivatives, endomorphins possess significant potential as analgesics with reduced side effects and risk of addiction. [4]

Contents

Opioids and receptors

Endomorphins belong to the opiate class of neuropeptides (protein neurotransmitters). Opiates are ligands that bind to opioid receptors [5] and exist endogenously and synthetically. [1] Endogenous opiates include endorphins, enkephalins, dynorphins, and endomorphins. [5]

Transcription and translation of opiate-encoding genes results in the formation of pre-propeptide opiate precursors, which are modified in the endoplasmic reticulum to become propeptide opiate precursors, transferred to the golgi apparatus, and further modified into the opiate product. [5] The exact pre-propeptide precursors of endomorphins have not been identified. [4] 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 the G protein-coupled receptor family and include μ, κ, δ, and nociceptinorphanin-FQ receptors. [6] While activation of opiate receptors initiates a diverse array of responses, opiates typically serve as depressants, and are widely used and developed as analgesics. Additionally, opiate malfunction has been linked to schizophrenia and autism. [5] Endomorphins demonstrate high selectivity and affinity for the μ-opioid receptor, which functions in pain relief and intoxication. [1]

Structure

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. [2] The specific amino acids in these sequences dictate the folding and resultant behavior, namely the ability to bind μ-opioid receptors, of these molecules.

Function

Endomorphins maintain 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. [3] The elimination of calcium influx and facilitation of potassium ion efflux prevents neuronal depolarization, inhibits the generation of action potentials, and depresses the activity of excitatory neurons. [3] In other instances, endomorphin binding causes excitation, where its activation of phospholipase C and adenylyl cyclase initiates an increase in calcium ion concentration, cellular depolarization, and the release of norepinephrine and serotonin. [4]

The specific roles of endomorphins largely remain undetermined and depend upon the pathway in question. [3] Opioid systems influence the physiological processes of pain, reward, and stress. They also play roles in immune responses and the functions of the gastrointestinal, respiratory, cardiovascular, and neuroendocrine systems. [3]

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. [7]

Location

The location of endomorphin activity has been isolated using radioimmunoassay and immunocytochemistry within human, mice, rat, and monkey nervous systems. [2] Both endomorphin tetrapeptides can be found in certain areas of the brain. In the midbrain, endomorphin-1 can be found in the hypothalamus, thalamus, and striatum. Within the telencephalon, endomorphin-1 has been identified in the nucleus accumbens and lateral septum. In the hindbrain, more endomorphin-1 reactive neurons have been detected compared to endomorphin-2. [2] Alternately, endomorphin-2 is predominantly found in the spinal cord, specifically in presynaptic terminals of afferent neurons in the dorsal horn region. It has been found co-localized with calcitonin as well as the pain-conveying neurotransmitter, substance P. Neither endomorphin-1 or 2 have been identified in the amygdala or the hippocampus. [2]

m-opioid Receptor Mu-opioid receptor (GPCR).png
μ-opioid Receptor

Clinical application

In addition to endomorphins, morphine and morphine-like opiates target the μ-opioid receptor. Thus, endomorphins pose significant potential as analgesics and morphine substitutes. [4] 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 as vasodilation, respiratory depression, urinary retention, and gastrointestinal reaction develop. [4] However, the endomorphin-induced side effects prove slightly less severe than those of the morphine-derived analgesics commonly used today. Additionally, endomorphins potentially produce more powerful analgesic effects than their morphine-derived counterparts. [4]

Despite their pharmaceutical aptitude, the low membrane permeability and vulnerability to enzymatic degradation of endomorphins limits their incorporation into drugs. As a result, endomorphin analogues are being generated to allow transport across the blood brain barrier, increase stability, and reduce side effects. [8] Two endomorphin modifications that approach these problems include glycosylation and lipidation. Glycosylation adds carbohydrate groups to the endomorphin molecules, allowing them to pass membranes through glucose transporters. Lipidation adds lipoamino acids or fatty acids to the endomorphin molecules, increasing hydrophobicity and, therefore, membrane permeability of the molecules. [8]

Related Research Articles

<span class="mw-page-title-main">Neurotransmitter</span> Chemical substance that enables neurotransmission

A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell.

Endorphins are peptides produced in the brain that block the perception of pain and increase feelings of wellbeing. They are produced and stored in the pituitary gland of the brain. Endorphins are endogenous painkillers often produced in the brain and adrenal medulla during physical exercise or orgasm and inhibit pain, muscle cramps, and relieve stress.

<span class="mw-page-title-main">Opioid receptor</span> Group of biological receptors

Opioid receptors are a group of inhibitory G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostatin receptors (SSTRs). Opioid receptors are distributed widely in the brain, in the spinal cord, on peripheral neurons, and digestive tract.

β-Endorphin Peptide hormone in humans

β-Endorphin (beta-endorphin) is an endogenous opioid neuropeptide and peptide hormone that is produced in certain neurons within the central nervous system and peripheral nervous system. It is one of three endorphins that are produced in humans, the others of which include α-endorphin and γ-endorphin.

<span class="mw-page-title-main">Opioid peptide</span> Class of peptides that bind to opioid receptors

Opioid peptides or opiate peptides are peptides that bind to opioid receptors in the brain; opiates and opioids mimic the effect of these peptides. Such peptides may be produced by the body itself, for example endorphins. The effects of these peptides vary, but they all resemble those of opiates. Brain opioid peptide systems are known to play an important role in motivation, emotion, attachment behaviour, the response to stress and pain, control of food intake, and the rewarding effects of alcohol and nicotine.

A tetrapeptide is a peptide, classified as an oligopeptide, since it only consists of four amino acids joined by peptide bonds. Many tetrapeptides are pharmacologically active, often showing affinity and specificity for a variety of receptors in protein-protein signaling. Present in nature are both linear and cyclic tetrapeptides (CTPs), the latter of which mimics protein reverse turns which are often present on the surface of proteins and druggable targets. Tetrapeptides may be cyclized by a fourth peptide bond or other covalent bonds.

<span class="mw-page-title-main">Met-enkephalin</span> Chemical compound

Met-enkephalin, also known as metenkefalin (INN), sometimes referred to as opioid growth factor (OGF), is a naturally occurring, endogenous opioid peptide that has opioid effects of a relatively short duration. It is one of the two forms of enkephalin, the other being leu-enkephalin. The enkephalins are considered to be the primary endogenous ligands of the δ-opioid receptor, due to their high potency and selectivity for the site over the other endogenous opioids.

<span class="mw-page-title-main">Nociceptin receptor</span> Protein-coding gene in the species Homo sapiens

The nociceptin opioid peptide receptor (NOP), also known as the nociceptin/orphanin FQ (N/OFQ) receptor or kappa-type 3 opioid receptor, is a protein that in humans is encoded by the OPRL1 gene. The nociceptin receptor is a member of the opioid subfamily of G protein-coupled receptors whose natural ligand is the 17 amino acid neuropeptide known as nociceptin (N/OFQ). This receptor is involved in the regulation of numerous brain activities, particularly instinctive and emotional behaviors. Antagonists targeting NOP are under investigation for their role as treatments for depression and Parkinson's disease, whereas NOP agonists have been shown to act as powerful, non-addictive painkillers in non-human primates.

Leu-enkephalin is an endogenous opioid peptide neurotransmitter with the amino acid sequence Tyr-Gly-Gly-Phe-Leu that is found naturally in the brains of many animals, including humans. It is one of the two forms of enkephalin; the other is met-enkephalin. The tyrosine residue at position 1 is thought to be analogous to the 3-hydroxyl group on morphine. Leu-enkephalin has agonistic actions at both the μ- and δ-opioid receptors, with significantly greater preference for the latter. It has little to no effect on the κ-opioid receptor.

Big dynorphin is an endogenous opioid peptide of the dynorphin family that is composed of both dynorphin A and dynorphin B. Big dynorphin has the amino acid sequence: Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Asn-Gln-Lys-Arg-Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Gln-Phe-Lys-Val-Val-Thr. It has nociceptive and anxiolytic-like properties, as well as effects on memory in mice.

DAMGO is a synthetic opioid peptide with high μ-opioid receptor specificity. It was synthesized as a biologically stable analog of δ-opioid receptor-preferring endogenous opioids, leu- and met-enkephalin. Structures of DAMGO bound to the μ opioid receptor reveal a very similar binding pose to morphinans.

<span class="mw-page-title-main">Opiate</span> Substance derived from opium

An opiate is an alkaloid substance derived from opium. It differs from the similar term opioid in that the latter is used to designate all substances, both natural and synthetic, that bind to opioid receptors in the brain. Opiates are alkaloid compounds naturally found in the opium poppy plant Papaver somniferum. The psychoactive compounds found in the opium plant include morphine, codeine, and thebaine. Opiates have long been used for a variety of medical conditions, with evidence of opiate trade and use for pain relief as early as the eighth century AD. Most opiates are considered drugs with moderate to high abuse potential and are listed on various "Substance-Control Schedules" under the Uniform Controlled Substances Act of the United States of America.

<span class="mw-page-title-main">Morphiceptin</span> Chemical compound

Morphiceptin is a tetrapeptide (Tyr-Pro-Phe-Pro-NH2) that is a selective μ-opioid receptor agonist. It is derived from β-casomorphin and has over 1,000 times selectivity for μ- over δ-opioid receptors. When injected intracerebroventricularly (into the ventricular system of the brain), morphiceptin had an analgesic ED50 of 1.7 nmol per animal. The analgesic effects of morphiceptin were reversed by naloxone, meaning that the analgesic effect is mediated by the μ-opioid receptor.

<span class="mw-page-title-main">Hemorphin-4</span> Endogenous opioid peptide

Hemorphin-4 is an endogenous opioid peptide of the hemorphin family which possesses antinociceptive properties and is derived from the β-chain of hemoglobin in the bloodstream. It is a tetrapeptide with the amino acid sequence Tyr-Pro-Trp-Thr. Hemorphin-4 has affinities for the μ-, δ-, and κ-opioid receptors that are in the same range as the structurally related β-casomorphins, although affinity to the κ-opioid receptor is markedly higher in comparison. It acts as an agonist at these sites. Hemorphin-4 also has inhibitory effects on angiotensin-converting enzyme (ACE), and as a result, may play a role in the regulation of blood pressure. Notably, inhibition of ACE also reduces enkephalin catabolism.

<span class="mw-page-title-main">Biphalin</span> Chemical compound

Biphalin is a dimeric enkephalin endogenous peptide (Tyr-D-Ala-Gly-Phe-NH)2 composed of two tetrapeptides derived from enkephalins, connected 'tail-to-tail' by a hydrazide bridge. The presence of two distinct pharmacophores confers on biphalin a high affinity for both μ and δ opioid receptors (with an EC50 of about 1–5 nM for both μ and δ receptors), therefore it has analgesic activity. Biphalin presents a considerable antinociceptive profile. In fact, when administered intracerebroventricularly in mice, biphalin displays a potency almost 7-fold greater than that of the ultra-potent alkaloid agonist, etorphine and 7000-fold greater than morphine; biphalin and morphine were found to be equipotent after intraperitoneal administration. The extraordinary in vivo potency shown by this compound is coupled with low side-effects, in particular, to produce no dependency in chronic use. For these reasons, several efforts have been carried out in order to obtain more information about structure-activity relationship (SAR). Results clearly indicate that, at least for μ receptor binding, the presence of two pharmacophores is not necessary; Tyr1 is indispensable for analgesic activity, while replacing Phe at the position 4 and 4' with non-aromatic, but lipophilic amino acids does not greatly change the binding properties and in general 4,4' positions are found to be important to design biphalin analogues with increased potency and modified μ/δ selectivity. The hydrazide linker is not fundamental for activity or binding, and it can be conveniently substituted by different conformationally constrained cycloaliphatic diamine linkers.

<span class="mw-page-title-main">CR665</span> Chemical compound

CR665 (H-D-Phe-D-Phe-D-Nle-D-Arg-NH-4-Picolyl), also known by the previous developmental code names FE-200665 and JNJ-38488502, is an all D-amino acid peptide that acts as a peripherally restricted κ-opioid receptor agonist. The selectivity for FE 200665 is 1/16,900/84,600 for the human κ, μ, and δ opioid receptors, respectively. The dose of FE 200665 required to produce motor impairment was 548 times higher than the dose required for antinociceptive activity. It is being developed for use by Cara Therapeutics under the code name CR665.

<span class="mw-page-title-main">Frakefamide</span> Opioid agonist peptide compound

Frakefamide (INN) is a synthetic, fluorinated linear tetrapeptide with the amino acid sequence Tyr-D-Ala-(p-F)Phe-Phe-NH2 which acts as a peripherally-specific, selective μ-opioid receptor agonist. Despite its inability to penetrate the blood-brain-barrier and enter the central nervous system, frakefamide has potent analgesic effects and, unlike centrally-acting opioids like morphine, does not produce respiratory depression, indicating that its antinociceptive effects are mediated by peripheral μ-opioid receptors. It was under development for the treatment of pain by AstraZeneca and Shire but was shelved after phase II clinical trials.

<span class="mw-page-title-main">Metkefamide</span> Chemical compound

Metkefamide (INN; LY-127,623), or metkephamid acetate (USAN), but most frequently referred to simply as metkephamid, is a synthetic opioid pentapeptide and derivative of [Met]enkephalin with the amino acid sequence Tyr-D-Ala-Gly-Phe-(N-Me)-Met-NH2. It behaves as a potent agonist of the δ- and μ-opioid receptors with roughly equipotent affinity, and also has similarly high affinity as well as subtype-selectivity for the κ3-opioid receptor.

<span class="mw-page-title-main">Endomorphin-1</span> Chemical compound

Endomorphin-1 (EM-1) (amino acid sequence Tyr-Pro-Trp-Phe-NH2) is an endogenous opioid peptide and one of the two endomorphins. It is a high affinity, highly selective agonist of the μ-opioid receptor, and along with endomorphin-2 (EM-2), has been proposed to be the actual endogenous ligand of the μ-receptor. EM-1 produces analgesia in animals and is equipotent with morphine in this regard. The gene encoding for EM-1 has not yet been identified, and it has been suggested that endomorphins could be synthesized by an enzymatic, non-ribosomal mechanism.

<span class="mw-page-title-main">Endomorphin-2</span> Chemical compound

Endomorphin-2 (EM-2) is an endogenous opioid peptide and one of the two endomorphins. It has the amino acid sequence Tyr-Pro-Phe-Phe-NH2. It is a high affinity, highly selective agonist of the μ-opioid receptor, and along with endomorphin-1 (EM-1), has been proposed to be the actual endogenous ligand of this receptor (that is, rather than the endorphins). Like EM-1, EM-2 produces analgesia in animals, but whereas EM-1 is more prevalent in the brain, EM-2 is more prevalent in the spinal cord. In addition, the action of EM-2 differs from that of EM-1 somewhat, because EM-2 additionally induces the release of dynorphin A and [Met]enkephalin in the spinal cord and brain by an unknown mechanism, which in turn go on to activate the κ- and δ-opioid receptors, respectively, and a portion of the analgesic effects of EM-2 is dependent on this action. Moreover, while EM-1 produces conditioned place preference, a measure of drug reward, EM-2 produces conditioned place aversion, an effect which is dynorphin A-dependent. Similarly to the case of EM-1, the gene encoding for EM-2 has not yet been identified.

References

  1. 1 2 3 Koob, George F. (2014). Drugs, Addiction, and the Brain. Academic Press. pp. 133–171. ISBN   978-0-12-386937-1.
  2. 1 2 3 4 5 6 Bodnar, Richard J (2018). "Endogenous Opiates and Behavior: 2016". Peptides. 101: 167–212. doi:10.1016/j.peptides.2018.01.011. PMID   29366859. S2CID   3542686.
  3. 1 2 3 4 5 Horvath, Gyöngyi (2000). "Endomorphin-1 and endomorphin-2: Pharmacology of the selective endogenous μ-opioid receptor agonists". Pharmacology & Therapeutics. 88 (3): 437–63. doi:10.1016/S0163-7258(00)00100-5. PMID   11337033.
  4. 1 2 3 4 5 6 Gu, Zheng-Hui; Wang, Bo; Kou, Zhen-Zhen; Bai, Yang; Chen, Tao; Dong, Yu-Lin; Li, Hui; Li, Yun-Qing (2017). "Endomorphins: Promising Endogenous Opioid Peptides for the Development of Novel Analgesics". Neurosignals. 25 (1): 98–116. doi: 10.1159/000484909 . PMID   29132133.
  5. 1 2 3 4 Purves (2018). Neuroscience. Sinauer Associates. p. 137. ISBN   978-1-60535-380-7.
  6. Lazarus, Lawrence H; Okada, Yoshio (2012). "Engineering endomorphin drugs: State of the art". Expert Opinion on Therapeutic Patents. 22 (1): 1–14. doi:10.1517/13543776.2012.646261. PMC   3253703 . PMID   22214283.
  7. Fichna, J; Janecka, A; Costentin, J; Do Rego, J.-C (2007). "The Endomorphin System and Its Evolving Neurophysiological Role". Pharmacological Reviews. 59 (1): 88–123. doi:10.1124/pr.59.1.3. PMID   17329549. S2CID   1512871.
  8. 1 2 Varamini, Pegah; Toth, Istvan (2013). "Lipid- and sugar-modified endomorphins: Novel targets for the treatment of neuropathic pain". Frontiers in Pharmacology. 4: 155. doi: 10.3389/fphar.2013.00155 . PMC   3862115 . PMID   24379782.