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{{Short description|Opioid analgesic drug}}
{{cs1 config|name-list-style=vanc}}
{{Drugbox
{{Drugbox
| Verifiedfields = changed
| Verifiedfields = changed
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| tradename =
| tradename =
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US = <!-- A / B / C / D / X -->
| pregnancy_category =
| pregnancy_category =
| legal_AU = S8
| legal_AU = S8
| legal_BR = A2
| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=2023-08-03 |access-date=2023-08-03 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=2023-04-04}}</ref>
| legal_CA = Schedule I
| legal_CA = Schedule I
| legal_UK =
| legal_UK =
| legal_US = Schedule I
| legal_US = Schedule I
| legal_DE = Anlage II
| legal_DE = Anlage II
| routes_of_administration = oral, injected
| routes_of_administration = [[Oral administration|By mouth]], injected


<!--Pharmacokinetic data-->
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<!--Chemical data-->
| C=16 | H=25 | N=3 | O=1
| C=16 | H=25 | N=3 | O=1
| molecular_weight = 275.39 g/mol
| smiles = O=C(N(c1ncccc1)C(CN2CCCCC2)C)CC
| smiles = O=C(N(c1ncccc1)C(CN2CCCCC2)C)CC
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
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}}
}}


'''Propiram''' ('''Algeril''', '''Dirame''', '''Bay 4503''') is a partial mu [[opioid]] receptor agonist and weak mu antagonist [[analgesic]] from the ampromide family of drugs. It was invented in 1963 in the United Kingdom by Bayer<ref>{{US Patent|3163654}}</ref> but was not widely marketed, although it saw some limited clinical use, especially in dentistry. Propiram reached [[Phase III clinical trial]]s in the United States and Canada.<ref>{{cite book | title = Drug Facts & Comparisons | edition = 56th | date = 2002}}</ref>
'''Propiram''' ('''Algeril''', '''Dirame''', '''Bay 4503''')<ref>US3163654A Pyridine derivatives and their preparation (n-tertiary aminoalkyl-n-acyl)-amino pyridines</ref> is a partial [[μ-opioid receptor]] agonist and weak μ antagonist [[analgesic]] from the ampromide family of drugs related to other drugs such as [[phenampromide]] and [[diampromide]]. It was invented in 1963 in the United Kingdom by Bayer<ref>{{US Patent|3163654}}</ref> but was not widely marketed, although it saw some limited clinical use, especially in dentistry. Propiram reached [[Phase III clinical trial]]s in the United States and Canada.<ref>{{cite book | title = Drug Facts & Comparisons | edition = 56th | date = 2002}}</ref>


==Pharmacology==
==Pharmacology==
Propiram exhibits weak opioid antagonist activity on the mu receptor—quite a bit weaker than its agonist effects—and the effect on kappa and delta opioid, sigma receptors, or the [[NMDA]] system are not well understood. Other drugs of the partial mu-opioid agonist/antagonist type include [[meptazinol]], [[buprenorphine]], [[butorphanol]], [[phenazocine]], [[nalbuphine]], [[pentazocine]], [[dezocine]] and its relatives.
Propiram exhibits weak opioid antagonist activity on the μ receptor—quite a bit weaker than its agonist effects—and the effect on [[kappa-opioid receptor|κ-]] and [[delta-opioid receptor|δ-opioid]], [[sigma receptor|σ-receptors]], or the [[NMDA]] system are not well understood. Other drugs of the partial μ-opioid agonist/antagonist type include [[meptazinol]], [[buprenorphine]], [[butorphanol]], [[phenazocine]], [[nalbuphine]], [[pentazocine]], [[dezocine]] and its relatives.


With about 10% of the analgesic potency of [[morphine]], 50&nbsp;mg of propiram is equivalent to about 60&nbsp;mg of codeine or 50&nbsp;mg of pentazocine. In many patients, propiram is an effective analgesic comparable to other drugs such as these as well as [[pethidine]], with a normal dose of around 50–100&nbsp;mg and a duration of action of 3 to 6 hours.<ref>{{cite journal | pmid = 7165237| year = 1982| author1 = Wilson| first1 = R. S.| title = Use of a new oral analgesic, propiram fumarate, in treating postoperative ocular pain| journal = Annals of Ophthalmology| volume = 14| issue = 12| pages = 1172–4| last2 = Landers| first2 = J. H.}}</ref> It is more potent and effective than codeine,<ref>{{cite journal | pmid = 6368614| year = 1984| author1 = Desjardins| first1 = P. J.| title = The relative analgesic efficacy of propiram fumarate, codeine, aspirin, and placebo in post-impaction dental pain| journal = Journal of Clinical Pharmacology| volume = 24| issue = 1| pages = 35–42| last2 = Cooper| first2 = S. A.| last3 = Gallegos| first3 = T. L.| last4 = Allwein| first4 = J. B.| last5 = Reynolds| first5 = D. C.| last6 = Kruger| first6 = G. O.| last7 = Beaver| first7 = W. T.| doi=10.1002/j.1552-4604.1984.tb01811.x}}</ref> and longer-lasting and with a faster onset of action compared to pethidine.<ref>{{cite journal | pmid = 7241356| year = 1981| author1 = Korduba| first1 = C. A.| title = Bioavailability of orally administered propiram fumarate in humans| journal = Journal of Pharmaceutical Sciences| volume = 70| issue = 5| pages = 521–3| last2 = Veals| first2 = J| last3 = Radwanski| first3 = E| last4 = Symchowicz| first4 = S| last5 = Chung| first5 = M| doi=10.1002/jps.2600700515}}</ref> Side effects include [[sedation]], [[dizziness]], [[nausea]] and [[vomiting]].<ref>{{cite journal | pmid = 7693433| year = 1993| author1 = Goa| first1 = K. L.| title = Propiram. A review of its pharmacodynamic and pharmacokinetic properties, and clinical use as an analgesic| journal = Drugs| volume = 46| issue = 3| pages = 428–45| last2 = Brogden| first2 = R. N.| doi=10.2165/00003495-199346030-00008}}</ref> Propiram has been available in oral, rectal, and injectable formulations, with bioavailability above 97% after oral administration. Many related compounds are known, although only propiram was ever commercialized.<ref>{{Cite journal | author = Hiltmann R, Hoffmeister F, Niemers E, Schlichting U, Wollweber H | title = 2-Acylaminopyridine derivatives with morphine agonistic and morphine antagonistic effects | journal = Arzneimittelforschung | date = 1973 | volume = 24 | issue = 4 | pages = 584–600| pmid = 4406861 }}</ref> The addition of a 4-phenyl group on the piperidine increases potency by a factor of 133 compared to the patent compound.<ref>Opiates by R. Lenz et al page 454</ref> Addition of a 3,3-dimethyl moiety to the piperidine ring increases potency by 45 compared to the title compound <ref>Opiates by Lenz et al page 455</ref> and 3D overlay using CHARMM<ref>https://www.charmm.org/charmm/?CFID=fb1a3b49-19aa-4696-bff2-fde5f1d3d44a&CFTOKEN=0</ref> shows that this class overlays the fentanyl scaffold perfectly.
With about 10% of the analgesic potency of [[morphine]], 50&nbsp;mg of propiram is equivalent to about 60&nbsp;mg of codeine or 50&nbsp;mg of pentazocine. In many patients, propiram is an effective analgesic comparable to other drugs such as these as well as [[pethidine]], with a normal dose of around 50–100&nbsp;mg and a duration of action of 3 to 6 hours.<ref>{{cite journal | vauthors = Wilson RS, Landers JH | title = Use of a new oral analgesic, propiram fumarate, in treating postoperative ocular pain | journal = Annals of Ophthalmology | volume = 14 | issue = 12 | pages = 1172–4 | date = December 1982 | pmid = 7165237 }}</ref> It is more potent and effective than codeine,<ref>{{cite journal | vauthors = Desjardins PJ, Cooper SA, Gallegos TL, Allwein JB, Reynolds DC, Kruger GO, Beaver WT | title = The relative analgesic efficacy of propiram fumarate, codeine, aspirin, and placebo in post-impaction dental pain | journal = Journal of Clinical Pharmacology | volume = 24 | issue = 1 | pages = 35–42 | date = January 1984 | pmid = 6368614 | doi = 10.1002/j.1552-4604.1984.tb01811.x | s2cid = 11070740 }}</ref> and longer-lasting and with a faster onset of action compared to pethidine.<ref>{{cite journal | vauthors = Korduba CA, Veals J, Radwanski E, Symchowicz S, Chung M | title = Bioavailability of orally administered propiram fumarate in humans | journal = Journal of Pharmaceutical Sciences | volume = 70 | issue = 5 | pages = 521–3 | date = May 1981 | pmid = 7241356 | doi = 10.1002/jps.2600700515 }}</ref> Side effects include [[sedation]], [[dizziness]], [[nausea]] and [[vomiting]].<ref>{{cite journal | vauthors = Goa KL, Brogden RN | title = Propiram. A review of its pharmacodynamic and pharmacokinetic properties, and clinical use as an analgesic | journal = Drugs | volume = 46 | issue = 3 | pages = 428–445 | date = September 1993 | pmid = 7693433 | doi = 10.2165/00003495-199346030-00008 | s2cid = 195691876 }}</ref> Propiram has been available in oral, rectal, and injectable formulations, with bioavailability above 97% after oral administration.
==Derivatives==
Many related compounds are known, although only propiram was ever commercialized.<ref>{{cite journal | vauthors = Hiltmann R, Hoffmeister F, Niemers E, Schlichting U, Wollweber H | title = [2-Acylaminopyridine derivatives with morphine agonistic and morphine antagonistic effects] | journal = Arzneimittel-Forschung | volume = 24 | issue = 4 | pages = 584–600 | date = April 1974 | pmid = 4406861 }}</ref> The addition of a 4-phenyl group on the piperidine increases potency by a factor of 133x compared to the parent compound. Addition of a 3,3-dimethyl moiety to the piperidine ring increases potency by 45x compared to the title compound <ref>Wollweber H. Stereochemische Untersuchungen über Arzneimittel. ''European Journal of Medicinal Chemistry'' 1982; 17: 125–133.</ref> and 3D overlay using CHARMM shows that this class overlays the fentanyl scaffold in the positioning of aryl groups, basic nitrogen and amide moieties perfectly.
[[Image:Propiram-derivatives_structure.png|280px|thumb|left|3,3-Dimethylpropiram, CAS# 24639-20-1, and 4-Phenylpropiram, CAS# 54152-81-7]]{{clear-left}}


==Regulation==
==Regulation==
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[[Category:Opioids]]
[[Category:Opioids]]
[[Category:Pyridines]]
[[Category:2-Pyridyl compounds]]
[[Category:Piperidines]]
[[Category:1-Piperidinyl compounds]]
[[Category:Propionamides]]
[[Category:Propionamides]]

Latest revision as of 11:34, 12 January 2024

Propiram
Clinical data
Routes of
administration		By mouth, injected
ATC code
  • none
Legal status
Legal status
Pharmacokinetic data
Bioavailability97%
Elimination half-life5.2 hours
Identifiers
  • N-(1-Methyl-2-piperidin-1-ylethyl)-N-pyridin-2-ylpropanamide
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
ECHA InfoCard100.036.144 Edit this at Wikidata
Chemical and physical data
FormulaC16H25N3O
Molar mass275.396 g·mol−1
3D model (JSmol)
  • O=C(N(c1ncccc1)C(CN2CCCCC2)C)CC
  • InChI=1S/C16H25N3O/c1-3-16(20)19(15-9-5-6-10-17-15)14(2)13-18-11-7-4-8-12-18/h5-6,9-10,14H,3-4,7-8,11-13H2,1-2H3 checkY
  • Key:ZBAFFZBKCMWUHM-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Propiram (Algeril, Dirame, Bay 4503)[2] is a partial μ-opioid receptor agonist and weak μ antagonist analgesic from the ampromide family of drugs related to other drugs such as phenampromide and diampromide. It was invented in 1963 in the United Kingdom by Bayer[3] but was not widely marketed, although it saw some limited clinical use, especially in dentistry. Propiram reached Phase III clinical trials in the United States and Canada.[4]

Pharmacology

[edit]

Propiram exhibits weak opioid antagonist activity on the μ receptor—quite a bit weaker than its agonist effects—and the effect on κ- and δ-opioid, σ-receptors, or the NMDA system are not well understood. Other drugs of the partial μ-opioid agonist/antagonist type include meptazinol, buprenorphine, butorphanol, phenazocine, nalbuphine, pentazocine, dezocine and its relatives.

With about 10% of the analgesic potency of morphine, 50 mg of propiram is equivalent to about 60 mg of codeine or 50 mg of pentazocine. In many patients, propiram is an effective analgesic comparable to other drugs such as these as well as pethidine, with a normal dose of around 50–100 mg and a duration of action of 3 to 6 hours.[5] It is more potent and effective than codeine,[6] and longer-lasting and with a faster onset of action compared to pethidine.[7] Side effects include sedation, dizziness, nausea and vomiting.[8] Propiram has been available in oral, rectal, and injectable formulations, with bioavailability above 97% after oral administration.

Derivatives

[edit]

Many related compounds are known, although only propiram was ever commercialized.[9] The addition of a 4-phenyl group on the piperidine increases potency by a factor of 133x compared to the parent compound. Addition of a 3,3-dimethyl moiety to the piperidine ring increases potency by 45x compared to the title compound [10] and 3D overlay using CHARMM shows that this class overlays the fentanyl scaffold in the positioning of aryl groups, basic nitrogen and amide moieties perfectly.

3,3-Dimethylpropiram, CAS# 24639-20-1, and 4-Phenylpropiram, CAS# 54152-81-7

Regulation

[edit]

Propiram is currently a Schedule I/Narcotic controlled substance in the United States with an ACSCN of 9649 and a zero annual aggregate manufacturing quota as of 2014. It has been almost exclusively formulated as the fumarate salt.

References

[edit]
  1. ^ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-03.
  2. ^ US3163654A Pyridine derivatives and their preparation (n-tertiary aminoalkyl-n-acyl)-amino pyridines
  3. ^ U.S. patent 3,163,654
  4. ^ Drug Facts & Comparisons (56th ed.). 2002.
  5. ^ Wilson RS, Landers JH (December 1982). "Use of a new oral analgesic, propiram fumarate, in treating postoperative ocular pain". Annals of Ophthalmology. 14 (12): 1172–4. PMID 7165237.
  6. ^ Desjardins PJ, Cooper SA, Gallegos TL, Allwein JB, Reynolds DC, Kruger GO, Beaver WT (January 1984). "The relative analgesic efficacy of propiram fumarate, codeine, aspirin, and placebo in post-impaction dental pain". Journal of Clinical Pharmacology. 24 (1): 35–42. doi:10.1002/j.1552-4604.1984.tb01811.x. PMID 6368614. S2CID 11070740.
  7. ^ Korduba CA, Veals J, Radwanski E, Symchowicz S, Chung M (May 1981). "Bioavailability of orally administered propiram fumarate in humans". Journal of Pharmaceutical Sciences. 70 (5): 521–3. doi:10.1002/jps.2600700515. PMID 7241356.
  8. ^ Goa KL, Brogden RN (September 1993). "Propiram. A review of its pharmacodynamic and pharmacokinetic properties, and clinical use as an analgesic". Drugs. 46 (3): 428–445. doi:10.2165/00003495-199346030-00008. PMID 7693433. S2CID 195691876.
  9. ^ Hiltmann R, Hoffmeister F, Niemers E, Schlichting U, Wollweber H (April 1974). "[2-Acylaminopyridine derivatives with morphine agonistic and morphine antagonistic effects]". Arzneimittel-Forschung. 24 (4): 584–600. PMID 4406861.
  10. ^ Wollweber H. Stereochemische Untersuchungen über Arzneimittel. European Journal of Medicinal Chemistry 1982; 17: 125–133.
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