Β-Endorphin

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β-Endorphin
Beta-endorphin.png
Beta endorphin 3D stick.png
Names
IUPAC name
L-Tyrosylglycylglycyl-L-phenylalanyl-L-methionyl-L-threonyl-L-seryl-L-glutaminyl-L-lysyl-L-seryl-L-glutaminyl-L-threonyl-L-prolyl-L-leucyl-L-valyl-L-threonyl-L-leucyl-L-phenylalanyl-L-lysyl-L-asparaginyl-L-alanyl-L-isoleucyl-L-isoleucyl-L-lysyl-L-asparaginyl-L-alanyl-L-tyrosyl-L-lysyl-L-lysylglycyl-L-glutamine
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
ECHA InfoCard 100.056.646 OOjs UI icon edit-ltr-progressive.svg
PubChem CID
UNII
  • InChI=1S/C158H253N41O44S/c1-17-84(9)126(153(237)184-102(44-29-34-65-163)137(221)188-112(74-120(168)210)142(226)173-86(11)131(215)185-110(73-94-48-52-96(206)53-49-94)146(230)179-99(41-26-31-62-160)135(219)177-98(40-25-30-61-159)134(218)172-78-124(214)175-106(158(242)243)56-59-119(167)209)195-154(238)127(85(10)18-2)194-132(216)87(12)174-143(227)113(75-121(169)211)187-136(220)100(42-27-32-63-161)180-147(231)111(72-92-38-23-20-24-39-92)186-144(228)107(68-81(3)4)190-155(239)129(89(14)203)197-152(236)125(83(7)8)193-148(232)108(69-82(5)6)189-151(235)116-45-35-66-199(116)157(241)130(90(15)204)198-140(224)104(55-58-118(166)208)182-149(233)114(79-200)191-138(222)101(43-28-33-64-162)178-139(223)103(54-57-117(165)207)181-150(234)115(80-201)192-156(240)128(88(13)202)196-141(225)105(60-67-244-16)183-145(229)109(71-91-36-21-19-22-37-91)176-123(213)77-170-122(212)76-171-133(217)97(164)70-93-46-50-95(205)51-47-93/h19-24,36-39,46-53,81-90,97-116,125-130,200-206H,17-18,25-35,40-45,54-80,159-164H2,1-16H3,(H2,165,207)(H2,166,208)(H2,167,209)(H2,168,210)(H2,169,211)(H,170,212)(H,171,217)(H,172,218)(H,173,226)(H,174,227)(H,175,214)(H,176,213)(H,177,219)(H,178,223)(H,179,230)(H,180,231)(H,181,234)(H,182,233)(H,183,229)(H,184,237)(H,185,215)(H,186,228)(H,187,220)(H,188,221)(H,189,235)(H,190,239)(H,191,222)(H,192,240)(H,193,232)(H,194,216)(H,195,238)(H,196,225)(H,197,236)(H,198,224)(H,242,243)/t84-,85-,86-,87-,88+,89+,90+,97-,98-,99-,100-,101-,102-,103-,104-,105-,106-,107-,108-,109-,110-,111-,112-,113-,114-,115-,116-,125-,126-,127-,128-,129-,130-/m0/s1
    Key: WOPZMFQRCBYPJU-NTXHZHDSSA-N
  • InChI=1/C158H253N41O44S/c1-17-84(9)126(153(237)184-102(44-29-34-65-163)137(221)188-112(74-120(168)210)142(226)173-86(11)131(215)185-110(73-94-48-52-96(206)53-49-94)146(230)179-99(41-26-31-62-160)135(219)177-98(40-25-30-61-159)134(218)172-78-124(214)175-106(158(242)243)56-59-119(167)209)195-154(238)127(85(10)18-2)194-132(216)87(12)174-143(227)113(75-121(169)211)187-136(220)100(42-27-32-63-161)180-147(231)111(72-92-38-23-20-24-39-92)186-144(228)107(68-81(3)4)190-155(239)129(89(14)203)197-152(236)125(83(7)8)193-148(232)108(69-82(5)6)189-151(235)116-45-35-66-199(116)157(241)130(90(15)204)198-140(224)104(55-58-118(166)208)182-149(233)114(79-200)191-138(222)101(43-28-33-64-162)178-139(223)103(54-57-117(165)207)181-150(234)115(80-201)192-156(240)128(88(13)202)196-141(225)105(60-67-244-16)183-145(229)109(71-91-36-21-19-22-37-91)176-123(213)77-170-122(212)76-171-133(217)97(164)70-93-46-50-95(205)51-47-93/h19-24,36-39,46-53,81-90,97-116,125-130,200-206H,17-18,25-35,40-45,54-80,159-164H2,1-16H3,(H2,165,207)(H2,166,208)(H2,167,209)(H2,168,210)(H2,169,211)(H,170,212)(H,171,217)(H,172,218)(H,173,226)(H,174,227)(H,175,214)(H,176,213)(H,177,219)(H,178,223)(H,179,230)(H,180,231)(H,181,234)(H,182,233)(H,183,229)(H,184,237)(H,185,215)(H,186,228)(H,187,220)(H,188,221)(H,189,235)(H,190,239)(H,191,222)(H,192,240)(H,193,232)(H,194,216)(H,195,238)(H,196,225)(H,197,236)(H,198,224)(H,242,243)/t84-,85-,86-,87-,88+,89+,90+,97-,98-,99-,100-,101-,102-,103-,104-,105-,106-,107-,108-,109-,110-,111-,112-,113-,114-,115-,116-,125-,126-,127-,128-,129-,130-/m0/s1
    Key: WOPZMFQRCBYPJU-NTXHZHDSBY
  • CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](C)C(=O)N[C@@H](Cc1ccc(cc1)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](C)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H]3CCCN3C(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](Cc4ccccc4)NC(=O)CNC(=O)CNC(=O)[C@H](Cc5ccc(cc5)O)N
Properties
C158H251N39O46S
Molar mass 3465.03 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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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. [1] It is one of three endorphins that are produced in humans, the others of which include α-endorphin and γ-endorphin. [2]

There are multiple forms of β-endorphins with the full sequence of Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr-Leu-Phe-Lys-Asn-Ala-Ile-Ile-Lys-Asn-Ala-Tyr-Lys-Lys-Gly-Glu (31 amino acids) denoted as β-endorphin(1-31) and variants truncated to the first 26 and 27 amino acids as β-endorphin(1-26) and β-endorphin(1-27). [1] [3] [4] The first 16 amino acids are identical to α-endorphin. β-Endorphin is considered to be a part of the endogenous opioid and endorphin classes of neuropeptides; [1] all of the established endogenous opioid peptides contain the same N-terminal amino acid sequence, Tyr-Gly-Gly-Phe, followed by either -Met or -Leu. [1]

Function of β-endorphin has been known to be associated with hunger, thrill, pain, maternal care, sexual behavior, and reward cognition. In the broadest sense, β-endorphin is primarily utilized in the body to reduce stress and maintain homeostasis. In behavioral research, studies have shown that β-endorphin is released via volume transmission into the ventricular system in response to a variety of stimuli, and novel stimuli in particular. [5]

Formation and structure

β-Endorphin is found in neurons of the hypothalamus, as well as the pituitary gland. It is derived from β-lipotropin, which is produced in the pituitary gland from a larger peptide precursor, proopiomelanocortin (POMC). [6] POMC is cleaved into two neuropeptides, adrenocorticotropic hormone (ACTH) and β-lipotropin. [7] The formation of β-endorphin is then the result of cleavage of the C-terminal region of β-lipotropin, producing a 31 amino acid-long neuropeptide with an alpha-helical secondary structure. However, POMC also gives rise to other peptide hormones, including α- and γ-melanocyte-stimulating hormone (MSH), resulting from intracellular processing by internal enzymes known as prohormone convertases.

A significant factor that differentiates β-endorphin from other endogenous opioids is its high affinity for and lasting effect on μ-opioid receptors. [6] The structure of β-endorphin in part accounts for this through its resistance to proteolytic enzymes, as its secondary structure makes it less vulnerable to degradation. [6]

This diagram depicts the formation of b-endorphin from the proopiomelanocortin gene in the pituitary gland. Portions of the second and third exon of this gene make up the proopiomelanocortin protein. The cleavage of the C-terminal end of this protein produces b-lipotropin, which is then cleaved again to form b-endorphin. The proopiomelanocortin protein is also a precursor to other neuropeptides and hormones, such as adrenocorticotropic hormone. Beta Endorphin- Gene to Product Formation Diagram.jpg
This diagram depicts the formation of β-endorphin from the proopiomelanocortin gene in the pituitary gland. Portions of the second and third exon of this gene make up the proopiomelanocortin protein. The cleavage of the C-terminal end of this protein produces β-lipotropin, which is then cleaved again to form β-endorphin. The proopiomelanocortin protein is also a precursor to other neuropeptides and hormones, such as adrenocorticotropic hormone.
A skeletal diagram showing the amino acid sequence of beta-endorphin with each amino acid labeled. Beta endorphin AA label.svg
A skeletal diagram showing the amino acid sequence of beta-endorphin with each amino acid labeled.

Function and effects

β-Endorphin function is said to be divided into two main categories: local function and global function. Global function of β-endorphin is related to decreasing bodily stress and maintaining homeostasis resulting in pain management, reward effects, and behavioral stability. β-Endorphin in global pathways diffuse to different parts of the body through cerebral spinal fluid in the spinal cord, allowing for β-endorphin release to affect the peripheral nervous system. Localized function of β-endorphin results in release of β-endorphin in different brain regions such as the amygdala or the hypothalamus. [5] The two main methods by which β-endorphin is utilized in the body are peripheral hormonal action [8] and neuroregulation. β-endorphin and other enkephalins are often released with ACTH to modulate hormone system functioning. Neuroregulation by β-endorphin occurs through interference with the function of another neuropeptide, either by direct inhibition of neuropeptide release or induction of a signaling cascade that reduces a neuropeptide's effects. [7]

Opioid agonist

β-Endorphin is an agonist of the opioid receptors; it preferentially binds to the μ-opioid receptor. [1] Evidence suggests that it serves as a primary endogenous ligand for the μ-opioid receptor, [1] [9] the same receptor to which the chemicals extracted from opium, such as morphine, derive their analgesic properties. β-Endorphin has the highest binding affinity of any endogenous opioid for the μ-opioid receptor. [1] [6] [9] Opioid receptors are a class of G-protein coupled receptors, such that when β-endorphin or another opioid binds, a signaling cascade is induced in the cell. [10] Acetylation of the N-terminus of β-endorphin, however, inactivates the neuropeptide, preventing it from binding to its receptor. [6] The opioid receptors are distributed throughout the central nervous system and within the peripheral tissue of neural and non-neural origin. They are also located in high concentrations in the Periaqueductal gray, Locus coeruleus, and the Rostral ventromedial medulla. [11]

Voltage-dependent calcium channels (VDCCs) are important membrane proteins that mediate the depolarization of neurons, and play a major role in promoting the release of neurotransmitters. When endorphin molecules bind to opioid receptors, G proteins activate and dissociate into their constituent Gα and Gβγ sub-units. The Gβγ sub-unit binds to the intracellular loop between the two trans-membrane helices of the VDCC. When the sub-unit binds to the voltage-dependent calcium channel, it produces a voltage-dependent block, which inhibits the channel, preventing the flow of calcium ions into the neuron. Embedded in the cell membrane is also the G protein-coupled inwardly-rectifying potassium channel. When a Gβγ or Gα(GTP) molecule binds to the C-terminus of the potassium channel, it becomes active, and potassium ions are pumped out of the neuron. [12] [13] The activation of the potassium channel and subsequent deactivation of the calcium channel causes membrane hyperpolarization. This is when there is a change in the membrane's potential, so that it becomes more negative. The reduction in calcium ions causes a reduction of neurotransmitter release because calcium is essential for this event to occur. [14] This means that neurotransmitters such as glutamate and substance P cannot be released from the presynaptic terminal of the neurons. These neurotransmitters are vital in the transmission of pain, and as β-Endorphin reduces the release of these substances, there is a strong analgesic effect.

Pain management

β-Endorphin has been primarily studied for its influence on nociception (i.e., pain perception). β-endorphin modulates pain perception both in the central nervous system and the peripheral nervous system. When pain is perceived, pain receptors (nociceptors) send signals to the dorsal horn of the spinal cord and then up to the hypothalamus through the release of a neuropeptide called substance P. [7] [5] [15] [16] In the peripheral nervous system, this signal causes the recruitment of T-lymphocytes, white blood cells of the immune system, to the area where pain was perceived. [16] T-lymphocytes release β-endorphin in this localized region, allowing it to bind to opioid receptors, causing direct inhibition of substance P. [16] [17] In the central nervous system, β-endorphin binds to opioid receptors in the dorsal root and inhibits the release of substance P in the spinal cord, reducing the number of excitatory pain signals sent to the brain. [16] [15] The hypothalamus responds to the pain signal by releasing β-endorphin through the periaqueductal grey network, which mainly acts to inhibit the release of GABA, a neurotransmitter which prevents the release of dopamine. [7] [15] Thus, the inhibition of GABA release by β-endorphin allows for a greater release of dopamine, in part contributing to the analgesic effect of β-endorphin. [7] [15] The combination of these pathways reduces pain sensation, allowing for the body to stop a pain impulse once it has been sent.

β-Endorphin has approximately 18 to 33 times the analgesic potency of morphine, [18] though its hormonal effect is species dependent. [8]

Exercise

β-Endorphin release in response to exercise has been known and studied since at least the 1980s. [19] Studies have demonstrated that serum concentrations of endogenous opioids, in particular β-endorphin and β-lipotropin, increase in response to both acute exercise and training. [19] The release of β-endorphin during exercise is associated with a phenomenon colloquially known in popular culture as a runner's high . [20]

Sunlight

There is evidence that β-endorphin is released in response to ultraviolet radiation, either through sun exposure or artificial tanning. [21] This is thought to contribute to addiction behavior among excessive sunbathers and users of artificial tanning despite health risks.

Mechanism of action

β-Endorphin acts as an agonist that binds to various types of G protein–coupled receptors(GPCRs), most notably to the mu, delta, and kappa opioid receptors. The receptors are responsible for supra-spinal analgesia.[ medical citation needed ]

History

β-Endorphin was discovered in camel pituitary extracts by C.H. Li and David Chung. [22] The primary structure of β-endorphin was unknowingly determined 10 years earlier, when Li and colleagues analyzed the sequence of another neuropeptide produced in the pituitary gland, γ-lipotropin. They noticed that the C-terminus region of this neuropeptide was similar to that of some enkephalins, suggesting that it may have a similar function to these neuropeptides. The C-terminal sequence of γ-lipotropin turned out to be the primary sequence of the β-endorphin. [6]

Related Research Articles

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">Proopiomelanocortin</span> Mammalian protein found in Homo sapiens

Pro-opiomelanocortin (POMC) is a precursor polypeptide with 241 amino acid residues. POMC is synthesized in corticotrophs of the anterior pituitary from the 267-amino-acid-long polypeptide precursor pre-pro-opiomelanocortin (pre-POMC), by the removal of a 26-amino-acid-long signal peptide sequence during translation. POMC is part of the central melanocortin system.

Corticotropes are basophilic cells in the anterior pituitary that produce pro-opiomelanocortin (POMC) which undergoes cleavage to adrenocorticotropin (ACTH), β-lipotropin (β-LPH), and melanocyte-stimulating hormone (MSH). These cells are stimulated by corticotropin releasing hormone (CRH) and make up 15–20% of the cells in the anterior pituitary. The release of ACTH from the corticotropic cells is controlled by CRH, which is formed in the cell bodies of parvocellular neurosecretory cells within the paraventricular nucleus of the hypothalamus and passes to the corticotropes in the anterior pituitary via the hypophyseal portal system. Adrenocorticotropin hormone stimulates the adrenal cortex to release glucocorticoids and plays an important role in the stress response.

Dynorphins (Dyn) are a class of opioid peptides that arise from the precursor protein prodynorphin. When prodynorphin is cleaved during processing by proprotein convertase 2 (PC2), multiple active peptides are released: dynorphin A, dynorphin B, and α/β-neoendorphin. Depolarization of a neuron containing prodynorphin stimulates PC2 processing, which occurs within synaptic vesicles in the presynaptic terminal. Occasionally, prodynorphin is not fully processed, leading to the release of “big dynorphin.” “Big Dynorphin” is a 32-amino acid molecule consisting of both dynorphin A and dynorphin B.

<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.

<span class="mw-page-title-main">Arcuate nucleus</span>

The arcuate nucleus of the hypothalamus is an aggregation of neurons in the mediobasal hypothalamus, adjacent to the third ventricle and the median eminence. The arcuate nucleus includes several important and diverse populations of neurons that help mediate different neuroendocrine and physiological functions, including neuroendocrine neurons, centrally projecting neurons, and astrocytes. The populations of neurons found in the arcuate nucleus are based on the hormones they secrete or interact with and are responsible for hypothalamic function, such as regulating hormones released from the pituitary gland or secreting their own hormones. Neurons in this region are also responsible for integrating information and providing inputs to other nuclei in the hypothalamus or inputs to areas outside this region of the brain. These neurons, generated from the ventral part of the periventricular epithelium during embryonic development, locate dorsally in the hypothalamus, becoming part of the ventromedial hypothalamic region. The function of the arcuate nucleus relies on its diversity of neurons, but its central role is involved in homeostasis. The arcuate nucleus provides many physiological roles involved in feeding, metabolism, fertility, and cardiovascular regulation.

<span class="mw-page-title-main">Neuropeptide</span> Peptides released by neurons as intercellular messengers

Neuropeptides are chemical messengers made up of small chains of amino acids that are synthesized and released by neurons. Neuropeptides typically bind to G protein-coupled receptors (GPCRs) to modulate neural activity and other tissues like the gut, muscles, and heart.

<span class="mw-page-title-main">Enkephalin</span> Pentapeptide

An enkephalin is a pentapeptide involved in regulating nociception in the body. The enkephalins are termed endogenous ligands, as they are internally derived and bind to the body's opioid receptors. Discovered in 1975, two forms of enkephalin have been found, one containing leucine ("leu"), and the other containing methionine ("met"). Both are products of the proenkephalin gene.

<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.

Neuromodulation is the physiological process by which a given neuron uses one or more chemicals to regulate diverse populations of neurons. Neuromodulators typically bind to metabotropic, G-protein coupled receptors (GPCRs) to initiate a second messenger signaling cascade that induces a broad, long-lasting signal. This modulation can last for hundreds of milliseconds to several minutes. Some of the effects of neuromodulators include: altering intrinsic firing activity, increasing or decreasing voltage-dependent currents, altering synaptic efficacy, increasing bursting activity and reconfigurating synaptic connectivity.

Lipotropin is the name for two hormones produced by the cleavage of pro-opiomelanocortin (POMC). The anterior pituitary gland produces the pro-hormone POMC, which is then cleaved again to form adrenocorticotropin (ACTH) and β-lipotropin (β-LPH).

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

Endomorphins are considered to be natural opioid neurotransmitters central to pain relief. 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. 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. 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. 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.

<span class="mw-page-title-main">Corticotropin-like intermediate peptide</span> Chemical compound

Corticotropin-like intermediate [lobe] peptide (CLIP), also known as adrenocorticotropic hormone fragment 18-39, is a naturally occurring, endogenous neuropeptide with a docosapeptide structure and the amino acid sequence Arg-Pro-Val-Lys-Val-Tyr-Pro-Asn-Gly-Ala-Glu-Asp-Glu-Ser-Ala-Glu-Ala-Phe-Pro-Leu-Glu-Phe. CLIP is generated as a proteolyic cleavage product of adrenocorticotropic hormone (ACTH), which in turn is a cleavage product of proopiomelanocortin (POMC). Its physiological role has been investigated in various tissues, specifically in the central nervous system.

<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.

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.

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.

α-Endorphin Chemical compound

α-Endorphin (alpha-endorphin) is an endogenous opioid peptide with a length of 16 amino acids, and the amino acid sequence: Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr. With the use of mass spectrometry, Nicholas Ling was able to determine the primary sequence of a-endorphin.

Neoendorphins are a group of endogenous opioid peptides derived from the proteolytic cleavage of prodynorphin. They include α-neoendorphin and β-neoendorphin. The α-neoendorphin is present in greater amounts in the brain than β-neoendorphin. Both are products of the dynorphin gene, which also expresses dynorphin A, dynorphin A-(1-8), and dynorphin B. These opioid neurotransmitters are especially active in Central Nervous System receptors, whose primary function is pain sensation. These peptides all have the consensus amino acid sequence of Try-Gly-Gly-Phe-Met (met-enkephalin) or Tyr-Gly-Gly-Phe-Leu ( leu-enkephalin). Binding of neoendorphins to opioid receptors (OPR), in the dorsal root ganglion (DRG) neurons results in the reduction of time of calcium-dependent action potential. The α-neoendorphins bind OPRD1(delta), OPRK1(kappa), and OPRM1 (mu) and β-neoendorphin bind OPRK1.

<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">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

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    β-Endorphin (also a pituitary hormone) ...
    Opioid peptides are encoded by three distinct genes. These precursors include POMC, from which the opioid peptide β-endorphin and several nonopioid peptides are derived, as discussed earlier; proenkephalin, from which met-enkephalin and leu-enkephalin are derived; and prodynorphin, which is the precursor of dynorphin and related peptides. Although they come from different precursors, opioid peptides share significant amino acid sequence identity. Specifically, all of the well-validated endogenous opioids contain the same four N-terminal amino acids (Tyr-Gly-Gly-Phe), followed by either Met or Leu ... Among endogenous opioid peptides, β-endorphin binds preferentially to μ receptors. ... Shared opioid peptide sequences. Although they vary in length from as few as five amino acids (enkephalins) to as many as 31 (β-endorphin), the endogenous opioid peptides shown here contain a shared N-terminal sequence followed by either Met or Leu.
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    β-endorphin (POMC, P01189), [Met]enkephalin (PENK, P01210), [Leu]enkephalin (PENK, P01210) ...
    Comments: β-Endorphin is the highest potency endogenous ligand
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