Propiram (Algeril, Dirame, Bay 4503) is a partial mu

opioid Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid use ...

receptor agonist and weak mu antagonist analgesic from the ampromide family of drugs related to other drugs such as

phenampromide Phenampromide is an opioid analgesic from the ampromide family of drugs, related to other drugs such as propiram and diampromide. It was invented in the 1960s by American Cyanamid Co. Although never given a general release, it was trialled and ...

and

diampromide Diampromide is an opioid analgesic from the ampromide family of drugs, related to other drugs such as propiram and phenampromide. It was invented in the 1960s by American Cyanamid, and can be described as a ring-opened analogue of fentanyl. Diamp ...

. It was invented in 1963 in the United Kingdom by Bayer but was not widely marketed, although it saw some limited clinical use, especially in dentistry. Propiram reached

Phase III clinical trial The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases ...

s in the United States and Canada.

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 ''N''-methyl--aspartic acid or ''N''-methyl--aspartate (NMDA) is an amino acid derivative that acts as a specific agonist at the NMDA receptor mimicking the action of glutamate, the neurotransmitter which normally acts at that receptor. Unlike ...

system are not well understood. Other drugs of the partial mu-opioid agonist/antagonist type include

meptazinol Meptazinol (trade name Meptid) is an opioid analgesic developed by Wyeth in the 1970s. Indications for use in moderate to severe pain, most commonly used to treat pain in obstetrics (childbirth). Meptazinol is a 3-phenylazepane derivative, wher ...

buprenorphine Buprenorphine is an opioid used to treat opioid use disorder, acute pain, and chronic pain. It can be used under the tongue (sublingual), in the cheek (buccal), by injection (intravenous and subcutaneous), as a skin patch (transdermal ...

butorphanol 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 ...

, phenazocine,

nalbuphine Nalbuphine, sold under the brand names Nubain among others, is an opioid analgesic which is used in the treatment of pain. It is given by injection into a vein, muscle, or fat. Side effects of nalbuphine include sedation, sweatiness, clamm ...

pentazocine Pentazocine, sold under the brand name Talwin among others, is a painkiller used to treat moderate to severe pain. It is believed to work by activating (agonizing) κ-opioid receptors (KOR) and μ-opioid receptors (MOR). As such it is called an ...

, dezocine and its relatives. With about 10% of the analgesic potency of

morphine Morphine is a strong opiate that is found naturally in opium, a dark brown resin in poppies (''Papaver somniferum''). It is mainly used as a pain medication, and is also commonly used recreationally, or to make other illicit opioids. T ...

, 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 Pethidine, also known as meperidine and sold under the brand name Demerol among others, is a synthetic opioid pain medication of the phenylpiperidine class. Synthesized in 1938 as a potential anticholinergic agent by the German chemist Otto Eis ...

, with a normal dose of around 50–100 mg and a duration of action of 3 to 6 hours. It is more potent and effective than codeine, and longer-lasting and with a faster onset of action compared to pethidine. Side effects include sedation,

dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a common medical c ...

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...

and

vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteri ...

. 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. 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 Wollweber H. Stereochemische Untersuchungen über Arzneimittel. ''European Journal of Medicinal Chemistry'' 1982; 17: 125–133. 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.

Regulation

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 Salt is a mineral composed primarily of sodium chloride (NaCl), a chemical compound belonging to the larger class of salts; salt in the form of a natural crystalline mineral is known as rock salt or halite. Salt is present in vast quant ...

References

{{Opioidergics Opioids 2-Pyridyl compounds 1-Piperidinyl compounds Propionamides