Proglumide

Proglumide
Clinical data
Trade namesMilid
Other names(RS)-N2-benzoyl-N,N-dipropyl-α-glutamine
AHFS/Drugs.comInternational Drug Names
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Elimination half-life~24 hours
Identifiers
  • 4-Benzamido-5-(dipropylamino)-5-oxopentanoic acid
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.026.880 Edit this at Wikidata
Chemical and physical data
FormulaC18H26N2O4
Molar mass334.416 g·mol−1
3D model (JSmol)
  • CCCN(CCC)C(=O)C(CCC(=O)O)NC(=O)c1ccccc1
  • InChI=1S/C18H26N2O4/c1-3-12-20(13-4-2)18(24)15(10-11-16(21)22)19-17(23)14-8-6-5-7-9-14/h5-9,15H,3-4,10-13H2,1-2H3,(H,19,23)(H,21,22) ☒N
  • Key:DGMKFQYCZXERLX-UHFFFAOYSA-N ☒N
 ☒NcheckY (what is this?)  (verify)

Proglumide, sold under the brand name Milid, is a drug that inhibits gastrointestinal motility and reduces gastric secretions. It acts as a cholecystokinin antagonist,[1] which blocks both the CCKA and CCKB subtypes.[2] It was used mainly in the treatment of stomach ulcers,[3][4] although it has now been largely replaced by newer drugs for this application.

An interesting side effect of proglumide is that it enhances the analgesia produced by opioid drugs,[5] and can prevent or even reverse the development of tolerance to opioid drugs.[6][7] This can make it a useful adjuvant treatment to use alongside opioid drugs in the treatment of chronic pain conditions such as cancer, where opioid analgesics may be required for long periods and development of tolerance reduces clinical efficacy of these drugs.[8][9]

Proglumide has also been shown to act as a δ-opioid receptor (DOR) agonist, which may contribute to its analgesic effects.[10] However, other studies show that proglumide has low affinity to the μ-opioid receptor (MOR) and the κ-opioid receptor (KOR) (13% of MOR and 17% of KOR occupancy at 100 μM), but no affinity to DOR.[11] It is questionable whether this is clinically significant, since the concentration they used was very high, and the occupancies were low even at that point.

Proglumide also works as a placebo effect amplifier for pain conditions. When injected visibly to a subject, its analgesic effect is bigger than a similarly administered placebo. When injected secretly, it does not have any effect, whereas standard pain drugs have an effect, even if they are administered without the subject's awareness.[12] The supposed mechanism is an enhancement of the neural pathways of expectation as a result of dopamine and endogenous opioids being suddenly released throughout numerous structures of the brain and spinal cord.

The ventral tegmental area is the structure believed to mediate proglumide's analgesic and euphoric effects, however dozens of areas with a wide range of physical and psychological functions are implicated in the mediation of the placebo effect (this accounts for proglumide's ability to produce physically measurable effects on vital signs such as heart rate, blood pressure, respiration rate, and tidal volume which cannot be accounted for by its clinically insignificant δ-opioid affinity.

  1. ^ Bunney BS, Chiodo LA, Freeman AS (1985). "Further studies on the specificity of proglumide as a selective cholecystokinin antagonist in the central nervous system". Annals of the New York Academy of Sciences. 448 (1): 345–351. Bibcode:1985NYASA.448..345B. doi:10.1111/j.1749-6632.1985.tb29929.x. PMID 2862828. S2CID 28298172.
  2. ^ González-Puga C, García-Navarro A, Escames G, León J, López-Cantarero M, Ros E, Acuña-Castroviejo D (October 2005). "Selective CCK-A but not CCK-B receptor antagonists inhibit HT-29 cell proliferation: synergism with pharmacological levels of melatonin". Journal of Pineal Research. 39 (3): 243–250. doi:10.1111/j.1600-079X.2005.00239.x. PMID 16150104. S2CID 20187767.
  3. ^ Bergemann W, Consentius K, Braun HE, Hirschmann H, Marowski B, Munck A, et al. (April 1981). "[Duodenal ulcer - multicenter double-blind study with proglumide]". Medizinische Klinik. 76 (8): 226–229. PMID 7231338.
  4. ^ Tariq M, Parmar NS, Ageel AM (May 1987). "Gastric and duodenal antiulcer and cytoprotective effects of proglumide in rats". The Journal of Pharmacology and Experimental Therapeutics. 241 (2): 602–607. PMID 3572816.
  5. ^ McCleane GJ (2003). "The cholecystokinin antagonist proglumide enhances the analgesic effect of dihydrocodeine". The Clinical Journal of Pain. 19 (3): 200–201. doi:10.1097/00002508-200305000-00008. PMID 12792559. S2CID 29229782.
  6. ^ Watkins LR, Kinscheck IB, Mayer DJ (April 1984). "Potentiation of opiate analgesia and apparent reversal of morphine tolerance by proglumide". Science. 224 (4647): 395–396. Bibcode:1984Sci...224..395W. doi:10.1126/science.6546809. PMID 6546809.
  7. ^ Tang J, Chou J, Iadarola M, Yang HY, Costa E (June 1984). "Proglumide prevents and curtails acute tolerance to morphine in rats". Neuropharmacology. 23 (6): 715–718. doi:10.1016/0028-3908(84)90171-0. PMID 6462377. S2CID 33168040.
  8. ^ Bernstein ZP, Yucht S, Battista E, Lema M, Spaulding MB (May 1998). "Proglumide as a morphine adjunct in cancer pain management". Journal of Pain and Symptom Management. 15 (5): 314–320. doi:10.1016/s0885-3924(98)00003-7. PMID 9654837.
  9. ^ McCleane GJ (November 1998). "The cholecystokinin antagonist proglumide enhances the analgesic efficacy of morphine in humans with chronic benign pain". Anesthesia and Analgesia. 87 (5): 1117–1120. doi:10.1213/00000539-199811000-00025. PMID 9806692. S2CID 10735834.
  10. ^ Rezvani A, Stokes KB, Rhoads DL, Way EL (1987). "Proglumide exhibits delta opioid agonist properties". Alcohol and Drug Research. 7 (3): 135–146. PMID 3030338.
  11. ^ Gaudreau P, Lavigne GJ, Quirion R (May 1990). "Cholecystokinin antagonists proglumide, lorglumide and benzotript, but not L-364,718, interact with brain opioid binding sites". Neuropeptides. 16 (1): 51–55. doi:10.1016/0143-4179(90)90029-X. PMID 2174522. S2CID 25646937.
  12. ^ Benedetti F, Amanzio M, Maggi G (November 1995). "Potentiation of placebo analgesia by proglumide". Lancet. 346 (8984): 1231. doi:10.1016/S0140-6736(95)92938-X. PMID 7475687.