Pages in category "Kappa agonists"
The following 76 pages are in this category, out of 76 total. This list may not reflect recent changes (learn more).
The following 76 pages are in this category, out of 76 total. This list may not reflect recent changes (learn more).
1. Pethidine – Pethidine, also known as meperidine and Demerol, is a synthetic opioid pain medication of the phenylpiperidine class. Synthesized in 1939 as an anticholinergic agent by the German chemist Otto Eisleb, its analgesic properties were first recognized by Otto Schaumann while working for IG Farben. Pethidine is indicated for the treatment of moderate to severe pain, for much of the 20th century, pethidine was the opioid of choice for many physicians, in 1975, 60% of doctors prescribed it for acute pain and 22% for chronic severe pain. The norpethidine metabolite was found to have effects, so pethidine could, unlike most opioids. Pethidine is in Schedule II of the Controlled Substances Act 1970 of the United States as a Narcotic with ACSCN9230 with a 6250 kilo aggregate manufacturing quota as of 2014. The free base conversion ratio for salts includes 0.87 for the hydrochloride and 0.84 for the hydrobromide. The A, B, and C intermediates in production of pethidine are also controlled and it is listed under the Single Convention for the Control of Narcotic Substances 1961 and is controlled in most countries in the same fashion as is morphine. It is still used in the United Kingdom and New Zealand. Pethidine is the preferred painkiller for diverticulitis, because it decreases intestinal intraluminal pressure, the adverse effects of pethidine administration are primarily those of the opioids as a class, nausea, vomiting, sedation, dizziness, diaphoresis, urinary retention, and constipation. Unlike other opioids, it does not cause miosis because of its anticholinergic properties, overdose can cause muscle flaccidity, respiratory depression, obtundation, cold and clammy skin, hypotension, and coma. A narcotic antagonist such as naloxone is indicated to reverse respiratory depression, serotonin syndrome has occurred in patients receiving concurrent antidepressant therapy with selective serotonin reuptake inhibitors or monoamine oxidase inhibitors. Convulsive seizures sometimes observed in patients receiving parenteral pethidine on a chronic basis have been attributed to accumumulation in plasma of the metabolite norpethidine, fatalities have occurred following either oral or intravenous pethidine overdose. Pethidine has serious interactions that can be dangerous with monoamine oxidase inhibitors, such patients may suffer agitation, delirium, headache, convulsions, and/or hyperthermia. Fatal interactions have been reported including the death of Libby Zion and it is thought to be caused by an increase in cerebral serotonin concentrations. It is probable that pethidine can also interact with a number of medications, including muscle relaxants, some antidepressants, benzodiazepines. Like morphine, pethidine exerts its effects by acting as an agonist at the μ-opioid receptor. Pethidine is often employed in the treatment of postanesthetic shivering, the pharmacologic mechanism of this antishivering effect is not fully understood, but it may involve the stimulation of κ-opioid receptors. Pethidine has structural similarities to atropine and other alkaloids and may have some of their effects
2. Salvinorin A – Salvinorin A is the main active psychotropic molecule in Salvia divinorum, a Mexican plant which has a long history of use as an entheogen by indigenous Mazatec shamans. Salvinorin A is considered a dissociative and it is structurally distinct from other naturally occurring hallucinogens because it contains no nitrogen atoms, hence, it is not an alkaloid but a terpenoid. It also differs in subjective experience, compared to other hallucinogens, Salvinorin A can produce psychoactive experiences in humans with a typical duration of action being several minutes to an hour or so, depending on the method of ingestion. Salvinorin A is found several other structurally related salvinorins. It acts as an opioid receptor agonist and is the first known compound acting on this receptor that is not an alkaloid. Salvinorin A was first described and named in 1982 by Alfredo Ortega and they used a combination of spectroscopy and x-ray crystallography to determine the chemical structure of the compound, which was shown to have a bicyclic diterpene structure. Around the same time, Leander Julián Valdés III independently isolated the molecule as part of his PhD research, Valdés named the chemical divinorum, and also isolated an analog that he named divinorum B. The naming was subsequently corrected to salvinorin A and B after the work was published in 1984, Salvinorin A is a trans-neoclerodane diterpenoid with the chemical formula C23H28O8. Unlike other known opioid-receptor ligands, salvinorin A is not an alkaloid as it not contain a basic nitrogen atom. Salvinorin A has no action at the 5-HT2A serotonin receptor, the molecular target responsible for the actions of classical psychedelics such as LSD. Salvinorin A is active at doses as low as 200 µg, synthetic chemicals, such as LSD, can be more potent. Research has shown that salvinorin A is a potent κ-opioid receptor agonist and it has a high affinity for the receptor, indicated by the low dissociation constant of 1.0 nanomolar. It has been reported that the effects of salvinorin A in mice are blocked by κ-opioid receptor antagonists. In addition, salvinorin A has recently found to act as a D2 receptor partial agonist, with an affinity of 5–10 nM, an intrinsic activity of 40–60%. This suggests that the D2 receptor may play an important role in its effects. Salvinorin As potency should not be confused with toxicity, mice chronically given dosages many times that of what humans are exposed to did not show signs of organ damage. Interestingly, salvinorin A shows atypical properties as an agonist of the KOR relative to other KOR agonists, like most other KOR agonists, salvinorin A does produce effects such as sedation, psychotomimesis, dysphoria/aversion, and anhedonia/depression however. The drug has been not to produce diuresis in mice
3. Mianserin – Mianserin is a psychoactive drug of the tetracyclic antidepressant therapeutic family. It is classified as a noradrenergic and specific serotonergic antidepressant and has antidepressant, anxiolytic, hypnotic, antiemetic, orexigenic and it is not approved for use in the US, but its analogue, mirtazapine, is. Mianserin was the first antidepressant to reach the UK market that was less dangerous than the tricyclic antidepressants in overdose, mianserin received TGA approval in May 1996. Similarly to its analogue, mirtazapine, mianserin has been tried as a strategy in treatment-resistant depression with some success. Mianserin has been tried, similarly to mirtazapine, as an adjunct in schizophrenia and has found to reduce negative and cognitive symptoms. Mianserin has demonstrated efficacy as a monotherapy for the treatment of Parkinsons disease psychosis in a clinical trial. Rare adverse effects include Oedema — the swelling of the bodys tissues due to fluid draining into said tissues, arthralgia Arthritis Rash Akathisia — a sense of inner restlessness that is often distressing for patients. Some cases of mianserin-induced blood dyscrasias have been fatal, gynaecomastia — abnormal breast enlargement in males. Pruritus — itchiness Hypertension Tachycardia Tinnitus — hearing ringing in the ears in the absence of an actual sound, conversely, CYP2D6 inducers would likely lead to reduced mianserin plasma concentrations and hence potentially diminish the therapeutic effects of mianserin. As a high affinity H1 receptor inverse agonist, mianserin has strong antihistamine effects, contrarily, it has negligible affinity for the mACh receptors, and thus lacks anticholinergic properties. It was recently found to be a weak κ-opioid receptor partial agonist, in addition, mianserin also appears to be a potent antagonist of the neuronal octopamine receptor. --Mianserin is approximately 200–300 times more active than its enantiomer --mianserin
4. Pentazocine – Pentazocine is a synthetically-prepared prototypical mixed agonist–antagonist narcotic drug of the benzomorphan class of opioids used to treat moderate to moderately severe pain. Pentazocine is sold under brand names, such as Fortral, Sosegon, Talwin NX, Talwin, Talwin PX, Fortwin. This compound may exist as one of two enantiomers, named -pentazocine and -pentazocine, -pentazocine is a κ-opioid receptor agonist, while -pentazocine is not, instead displaying a ten-fold greater affinity for the σ receptor. Usually, in its oral formulations, it is combined with naloxone so as to prevent people from crushing the tablets, dissolving them in a solvent, related drugs include phenazocine, dezocine, cyclazocine and several chemicals used in research on the central nervous system. Pentazocine is used primarily to treat pain, although its effects are subject to a ceiling effect. It has been discontinued by its sponsor in Australia, although it may be available through the special access scheme. In the 1970s, recreational drug users discovered that combining pentazocine with tripelennamine produced a euphoric sensation, since tripelennamine tablets are typically blue in color and brand-name Pentazocine is known as Talwin, the pentazocine/tripelennamine combination acquired the slang name Ts and blues. It was postulated that the efficacy observed was due to κ-opioid receptor activation-mediated amelioration of hyperdopaminergia in the reward pathways, minimal sedation and no side effects including psychotomimetic effects or worsening of psychosis were observed at the dose administered. Side effects are similar to those of morphine, but pentazocine, high dose may cause high blood pressure or high heart rate. It may also increase cardiac work after myocardial infarction when given intravenously, respiratory depression is a common side effect, but is subject to a ceiling effect, such that at a certain dose the degree of respiratory depression will no longer increase with dose increases. Likewise rarely it has associated with agranulocytosis, erythema multiforme. Severe injection site necrosis and sepsis has occurred with multiple injection of pentazocine lactate, in addition, animal studies have demonstrated that Pentazocine is tolerated less well subcutaneously than intramuscularly. Pentazocine was developed by the Sterling Drug Company, Sterling-Winthrop Research Institute, of Rensselaer and it was approved by the Food and Drug Administration in June 1967 after being favorably reviewed following testing on 12,000 patients in the United States. The analgesic compound was first made at Sterling in 1958, U. S. testing was conducted between 1961 and 1967. By mid 1967 Pentazocine was already being sold in Mexico, England, Pentazocine was originally classified in Schedule V under the Controlled Substances Act but a petition was filed with the D. E. A. on October 1,1971, to shift it to Schedule III. The petition was filed by Joseph L. Fink III, a pharmacist and that petition was accepted for review on November 10,1971 D. E. A. Pentazocine is still classified in Schedule IV under the Controlled Substances Act in the United States, although some states classify it in Schedule III. Internationally, pentazocine is a Schedule III drug under the Convention on Psychotropic Substances, Pentazocine has a DEA ACSCN of 9720, being a Schedule IV substance, the DEA does not assign an annual manufacturing quota for pentazocine for the United States
5. Norbuprenorphine – Norbuprenorphine is a major active metabolite of the opioid modulator buprenorphine. It is a μ-opioid, δ-opioid, and nociceptin receptor full agonist, in rats, unlike buprenorphine, norbuprenorphine produces marked respiratory depression but with very little antinociceptive effect. In explanation of these properties, norbuprenorphine has been found to be a high affinity P-glycoprotein substrate, and in accordance, shows very limited blood-brain-barrier penetration
6. Eluxadoline – It was approved for use in the United States in 2015. The drug originated from Janssen Pharmaceutica and was developed by Actavis, rare adverse effects, fatigue, bronchitis, viral gastroenteritis. Rare serious adverse effects include pancreatitis with an incidence of 0. 3% - higher incidence with 100 mg dose than with 75 mg dose. The risk is greater in those who do not have a gall bladder. Eluxadoline increases the concentrations of drugs which are OATP1B1 and BCRP substrates, also, coadministration of eluxadoline with rosuvastatin may increase the risk of rhabdomyolysis. Eluxadoline is a μ- and κ-opioid receptor agonist and δ-opioid receptor antagonist that acts locally in the nervous system. In the in vitro studies, eluxadoline was found to be transported by OAT3, OATP1B1, however, it was not to be transported by OCT1 POU2F1, OAT1 Organic anion transporter 1, OCT2, OATP1B3, P-gp, or BCRP. Multidrug resistance-associated protein 2 -vesicular accumulation of eluxadoline was observed, indicating that the drug is a substrate of MRP2, also in the in vitro studies, it was observed that eluxadoline is an in vivo substrate of OATP1B1, OAT3, and MRP2. Finally, no inhibition or induction of cytochrome P450 enzymes was observed, following a 100 mg dose of eluxadoline, the Cmax was about 2 to 4 ng/ml and AUC was 12-22 ng. h/ml. Eluxadoline has linear pharmacokinetics with no accumulation upon repeated twice daily dosing, taking eluxadoline with high fat meal decreased the Cmax by 50% and AUC by 60%. The synthesis of eluxadoline was extensively discussed in the patent No, wO2006099060 A2, with the title, Process for the preparation of opioid modulators which was published in Sept.2006 Asimadoline Axelopran Difenoxin Diphenoxylate Loperamide
7. Etorphine – Etorphine is a semi-synthetic opioid possessing an analgesic potency approximately 1, 000–3,000 times that of morphine. It was first prepared in 1960 from oripavine, which does not generally occur in opium poppy extract but rather the related plants Papaver orientale and it was later reproduced in 1963 by a research group at MacFarlan Smith in Gorgie, Edinburgh, led by Professor Kenneth Bentley. It can also be produced from thebaine, Etorphine is available legally only for veterinary use and is strictly governed by law. It is often used to immobilize elephants and other large mammals, diprenorphine, also known as Revivon, is an opioid receptor antagonist that can be administered in proportion to the amount of etorphine used to reverse its effects. Veterinary-strength etorphine is fatal to humans, for this reason the package as supplied to vets always includes the human antidote as well as etorphine. The LD50 in humans is 30 μg which led to the requirement that the medicine include an equal dose of an antidote, one of its main advantages is its speed of operation and, more importantly, the speed with which diprenorphine reverses the effects. The high incidence of side-effects, including severe depression, has caused etorphine to fall into disfavor in general veterinary practice. The high potency of etorphine means that sufficient etorphine can be administered to large mammals by projectile syringe. Large Animal Immobilon is a combination of etorphine plus acepromazine maleate, an etorphine antidote Large Animal Revivon contains mainly diprenorphine for animals and a human-specific naloxone-based antidote, which should be prepared prior to the etorphine. A 5–15 mg dose is enough to immobilize an African elephant, Etorphine is an extremely potent, non-selective full agonist of the μ-, δ-, and κ-opioid receptors. It also has relatively weak affinity for the nociceptin receptor, Etorphine has an LD50 of 30μg in humans. Its mu affinity is 0. 024nM compared with nalorphine nM0. 559Nm, diprenorphine Carfentanil has a Ki of 0.0000007. In Hong Kong, etorphine is regulated under Schedule 1 of Hong Kongs Chapter 134 Dangerous Drugs Ordinance and it can be used legally only by health professionals and for university research purposes. The substance can be given by pharmacists under a prescription, anyone who supplies the substance without prescription can be fined $10,000. The penalty for trafficking or manufacturing the substance is a $5,000,000 fine, possession of the substance for consumption without license from the Department of Health is illegal with a $1,000,000 fine and/or 7 years of jail time. In the Netherlands, etorphine is a list I drug of the Opium Law and it is used only for veterinary purposes in zoos to immobilize large animals. In the US, etorphine is listed as a Schedule I drug with an ACSCN of 9056, for both, the 2013 annual aggregate manufacturing quota for both was zero so presumably veterinary supplies of the hydrochloride are imported from Germany and/or the UK. In the UK, under the Misuse of Drugs Act 1971, etorphine is controlled as a Class A substance. com page on etorphine Etorphine, Molecule of the Month
8. Lofentanil – Lofentanil is one of the most potent opioid analgesics known and is an analogue of fentanyl, which was developed in 1960. It is most similar to the potent opioid carfentanil, only slightly more potent. Lofentanil can be described as 3-methylcarfentanil, or 3-methyl-4-carbomethoxyfentanyl, while 3-methylfentanyl is considerably more potent than fentanyl itself, lofentanil is only slightly stronger than carfentanil. This suggests that substitution at both the 3 and 4 positions of the piperidine ring introduces steric hindrance which prevents μ-opioid affinity from increasing much further. As with other 3-substituted fentanyl derivatives such as ohmefentanyl, the stereoisomerism of lofentanil is very important, lofentanil is very similar to carfentanil in effects, but has a longer duration of action. Side effects of fentanyl analogs are similar to those of fentanyl itself, which include itching, nausea, and potentially serious respiratory depression, side effects from lofentanil might be particularly problematic given its reportedly long duration of action. In addition to acting on the receptor, lofentanil has also been found to act as a full agonist of the κ-opioid receptor
9. 18-Methoxycoronaridine – In animal studies it has proved to be effective at reducing self-administration of morphine, cocaine, methamphetamine, nicotine and sucrose. The sites of action in the include the medial habenula, interpeduncular nucleus, dorsolateral tegmentum. It has also shown to produce anorectic effects in obese rats. 18-MC is in the stages of human testing by Savant HWP. In 2002 the research team started trying to raise funds for human trials, national Institute on Drug Abuse gave a $6.5 million grant in 2012 to California-based drug developer company Savant HWP for the human trials. These compounds were found to act as selective α3β4 nicotinic acetylcholine antagonists. Glick, Ramirez, RL, Livi, JM, Maisonneuve, 18-Methoxycoronaridine acts in the medial habenula and/or interpeduncular nucleus to decrease morphine self-administration in rats
10. Nalorphine – Nalorphine, also known as N-allyl-normorphine, is a mixed opioid agonist–antagonist with opioid antagonist and analgesic properties. It was introduced in 1954 and was used as an antidote to opioid overdose. Nalorphine was the opioid antagonist to be introduced, preceded by nalodeine in 1915 and followed by naloxone in 1960. Due to potent activation of the KOR, nalorphine produces side effects such as dysphoria, anxiety, confusion, and hallucinations, more recently, it has become much more commonplace to use ethyl chloroformate instead of cyanogen bromide for the Von Braun degradation demethylation step. See for example the list of phenyltropanes or the synthesis of paroxetine for further examples of this