Last updated
Clinical data
Routes of
ATC code
  • none
  • N-[[5-(2-Fluorophenyl)-1-methyl-2,3-dihydro-1,4-benzodiazepin-2-yl]methyl]thiophene-3-carboxamide
CAS Number
PubChem CID
ECHA InfoCard 100.073.052 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C22H20FN3OS
Molar mass 393.48 g·mol−1
3D model (JSmol)
  • O=C(NCC1N(c3ccccc3C(=N/C1)\c2ccccc2F)C)c4ccsc4
  • InChI=1S/C22H20FN3OS/c1-26-16(13-25-22(27)15-10-11-28-14-15)12-24-21(17-6-2-4-8-19(17)23)18-7-3-5-9-20(18)26/h2-11,14,16H,12-13H2,1H3,(H,25,27) Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Tifluadom is a benzodiazepine derivative with an unusual activity profile. [1] Unlike most benzodiazepines, tifluadom has no activity at the GABAA receptor, but instead is a selective agonist for the κ-opioid receptor. [2] It has potent analgesic [3] and diuretic [4] effects in animals, and also has sedative effects and stimulates appetite. [5] [6]

While tifluadom has several effects which might have potential uses in medicine, such as analgesia and appetite stimulation, κ-opioid agonists tend to produce undesirable effects in humans such as dysphoria and hallucinations, and so these drugs tend to only be used in scientific research. Dysphoric effects are similar to those seen when using other κ-opioid receptor agonists like pentazocine and salvinorin A, and can be considered the opposite of morphine-induced euphoria. As such, kappa agonists are believed to have very limited abuse potential.

See also

Related Research Articles

<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">Butorphanol</span> Opioid analgesic

Butorphanol is a morphinan-type synthetic agonist–antagonist opioid analgesic developed by Bristol-Myers. Butorphanol is most closely structurally related to levorphanol. Butorphanol is available as the tartrate salt in injectable, tablet, and intranasal spray formulations. The tablet form is only used in dogs, cats and horses due to low bioavailability in humans.

κ-opioid receptor Protein-coding gene in the species Homo sapiens, named for ketazocine

The κ-opioid receptor or kappa opioid receptor, abbreviated KOR or KOP for its ligand ketazocine, is a G protein-coupled receptor that in humans is encoded by the OPRK1 gene. The KOR is coupled to the G protein Gi/G0 and is one of four related receptors that bind opioid-like compounds in the brain and are responsible for mediating the effects of these compounds. These effects include altering nociception, consciousness, motor control, and mood. Dysregulation of this receptor system has been implicated in alcohol and drug addiction.

<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.

δ-opioid receptor Opioid receptor named for the mouse vas deferens, where it was first characterized

The ∆-opioid receptor, also known as delta opioid receptor or simply delta receptor, abbreviated DOR or DOP, is an inhibitory 7-transmembrane G-protein coupled receptor coupled to the G protein Gi/G0 and has enkephalins as its endogenous ligands. The regions of the brain where the ∆-opioid receptor is largely expressed vary from species model to species model. In humans, the ∆-opioid receptor is most heavily expressed in the basal ganglia and neocortical regions of the brain.

<span class="mw-page-title-main">Lofentanil</span> Opioid analgesic

Lofentanil or lofentanyl 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 highly potent opioid carfentanil (4-carbomethoxyfentanyl), 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, with some stereoisomers being much more potent than others.

<span class="mw-page-title-main">Nalfurafine</span> Antipruritic drug

Nalfurafine is an antipruritic that is marketed in Japan for the treatment of uremic pruritus in individuals with chronic kidney disease undergoing hemodialysis. It activates the κ-opioid receptor (KOR) and is potent, selective, and centrally active. It was the first selective KOR agonist approved for clinical use. It has also been dubiously referred to as the "first non-narcotic opioid drug" in history.

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

Homotaurine is a natural sulfonic acid found in seaweed. It is analogous to taurine, but with an extra carbon in its chain. It has GABAergic activity, apparently by mimicking GABA, which it resembles.

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

Naloxazone is an irreversible μ-opioid receptor antagonist which is selective for the μ1 receptor subtype. Naloxazone produces very long lasting antagonist effects as it forms a covalent bond to the active site of the μ-opioid receptor, thus making it impossible for the molecule to unbind and blocking the receptor permanently until the receptor is recycled by endocytosis.

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

Norbinaltorphimine is an opioid antagonist used in scientific research. It is one of the few opioid antagonists available that is highly selective for the κ-opioid receptor, and blocks this receptor without affecting the μ- or δ-opioid receptors, although it has less selectivity in vivo than when used in isolated tissues. nor-BNI blocks the effects of κ-opioid agonists in animal models, and produces antidepressant and antipanic-like effects.

<span class="mw-page-title-main">Agonist-antagonist</span>

In pharmacology the term agonist-antagonist or mixed agonist/antagonist is used to refer to a drug which under some conditions behaves as an agonist while under other conditions, behaves as an antagonist.

<span class="mw-page-title-main">Oxymorphazone</span> Opioid analgesic

Oxymorphazone is an opioid analgesic drug related to oxymorphone. Oxymorphazone is a potent and long acting μ-opioid agonist which binds irreversibly to the receptor, forming a covalent bond which prevents it from detaching once bound. This gives it an unusual pharmacological profile, and while oxymorphazone is only around half the potency of oxymorphone, with higher doses the analgesic effect becomes extremely long lasting, with a duration of up to 48 hours. However, tolerance to analgesia develops rapidly with repeated doses, as chronically activated opioid receptors are rapidly internalised by β-arrestins, similar to the results of non-covalent binding by repeated doses of agonists with extremely high binding affinity such as lofentanil.

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

Spiradoline (U-62066) is a drug which acts as a highly selective κ-opioid agonist. It has analgesic, diuretic, and antitussive effects, and produces subjective effects in animals similar to those of ketazocine and alazocine. The main effect in humans is sedation, along with analgesic and diuretic effects, but significant side effects such as dysphoria and hallucinations have stopped it from being used clinically.

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

Naltriben is a potent and selective antagonist for the delta opioid receptor, which is used in scientific research. It has similar effects to the more widely used δ antagonist naltrindole, but with different binding affinity for the δ1 and δ2 subtypes, which makes it useful for distinguishing the subtype selectivity of drugs acting at the δ receptors. It also acts as a κ-opioid agonist at high doses.

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

JDTic is a selective, long-acting ("inactivating") antagonist of the κ-opioid receptor (KOR). JDTic is a 4-phenylpiperidine derivative, distantly related structurally to analgesics such as pethidine and ketobemidone, and more closely to the MOR antagonist alvimopan. In addition, it is structurally distinct from other KOR antagonists such as norbinaltorphimine. JDTic has been used to create crystal structures of KOR [ PDB: 4DJH, 6VI4​].

<span class="mw-page-title-main">U-69,593</span> Chemical compound

U-69,593 is a drug which acts as a potent and selective κ1-opioid receptor agonist. In animal studies it has been shown to produce antinociception, anti-inflammation, anxiolysis, respiratory depression, and diuresis, while having little effect on gastrointestinal motility. It also inhibits the peripheral, though not central secretion of oxytocin and vasopressin in rats.

<span class="mw-page-title-main">GR-89696</span> Chemical compound

GR-89696 is a drug which acts as a highly selective κ-opioid agonist. It has been studied in various animal species, and has been described as selective for the κ2 subtype. Recent studies have suggested that GR-89696 and related κ2-selective agonists may be useful for preventing the itching which is a common side effect of conventional opioid analgesic drugs, without the additional side effects of non-selective kappa agonists. The structure bound to the κ-opioid receptor has been reported.

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

Quadazocine (WIN-44,441) is an opioid antagonist of the benzomorphan family which is used in scientific research. It acts as a silent antagonist at all three of the major opioid receptors—μ, κ, and δ, but with a significant preference in affinity for the μ receptor and the κ2 subtype. As such, it has been touted as a "κ2-selective" antagonist, though this is not entirely accurate on account of its similar affinity for the μ receptor. As would be expected, quadazocine reverses the effects of opioid agonists like morphine and fentanyl in animals.

<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">RB-64</span> Chemical compound

RB-64 is a semi-synthetic derivative of salvinorin A. It is an irreversible agonist, with a reactive thiocyanate group that forms a bond to the κ-opioid receptor (KOR), resulting in very high potency. It is functionally selective, activating G proteins more potently than β-arrestin-2. RB-64 has a bias factor of up to 96 and is analgesic with fewer of the side-effects associated with unbiased KOR agonists. The analgesia is long-lasting. Compared with unbiased agonists, RB-64 evokes considerably less receptor internalization.


  1. US 4325957,Zeugner H, Roemer D, Liepmann H, Milkowski W,"2-Acylaminomethyl-1,4-benzodiazepine derivatives and their salts and pharmaceutical compositions thereof",issued 20 April 1982, assigned to Abbott Products GmbH
  2. Römer D, Büscher HH, Hill RC, Maurer R, Petcher TJ, Zeugner H, Benson W, Finner E, Milkowski W, Thies PW (1982). "Unexpected opioid activity in a known class of drug". Life Sciences. 31 (12–13): 1217–20. doi:10.1016/0024-3205(82)90346-0. PMID   6292610.
  3. Genovese RF, Dykstra LA (November 1986). "Tifluadom's effects under electric shock titration and tail-immersion procedures in squirrel monkeys". Life Sciences. 39 (19): 1713–9. doi:10.1016/0024-3205(86)90089-5. PMID   3773641.
  4. Leander JD (March 1984). "Kappa opioid agonists and antagonists: effects on drinking and urinary output". Appetite. 5 (1): 7–14. doi:10.1016/s0195-6663(84)80044-6. PMID   6091543. S2CID   31380360.
  5. Jackson HC, Sewell RD (October 1984). "The role of opioid receptor sub-types in tifluadom-induced feeding". The Journal of Pharmacy and Pharmacology. 36 (10): 683–6. doi:10.1111/j.2042-7158.1984.tb04843.x. PMID   6150086. S2CID   13046110.
  6. Dykstra LA, Gmerek DE, Winger GA, Woods JH (August 1987). "Kappa opioids in rhesus monkeys. I. Diuresis, sedation, analgesia and discriminative stimulus effects". Journal of Pharmacology and Experimental Therapeutics. 242 (2): 413–20. PMID   3612543.