Pravadoline
Encyclopedia
Pravadoline is an antiinflammatory and analgesic
drug with an IC50
of 4.9 µM, related in structure to non-steroidal antinflammtory drugs (NSAIDs) such as indometacin
. It was developed in the 1980s as a new antiinflammatory and prostaglandin
synthesis inhibitor, acting through inhibition of the enzyme cyclooxygenase
(COX).
However pravadoline was found to exhibit unexpectedly strong analgesic effects, which appeared at doses ten times smaller than the effective anti-inflammatory dose and so could not be explained by its action as a COX inhibitor. These effects were not blocked by opioid antagonists
such as naloxone
, and it was eventually discovered that pravadoline represented the first compound from a novel class of cannabinoid agonist
s, the aminoalkylindoles.
Pravadoline was never developed for use as an analgesic, partly due to toxicity concerns (although these were later shown to be a result of the salt form that the drug had been prepared in rather than from the pravadoline itself), however the discovery of cannabinoid activity in this structurally novel family of drugs led to the discovery of several new cannabinoid agonists, including the drug WIN 55,212-2
which is now widely used in scientific research.
The antinociceptive activity of pravadoline cannot be explained by an opioid mechanism, because pravadoline-induced antinociception was not antagonized by naloxone (1mg/kg, s.c.) and pravadoline did not bind to the opioid receptor
s at concentrations up to 10μM.
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
drug with an IC50
IC50
The half maximal inhibitory concentration is a measure of the effectiveness of a compound in inhibiting biological or biochemical function. This quantitative measure indicates how much of a particular drug or other substance is needed to inhibit a given biological process by half...
of 4.9 µM, related in structure to non-steroidal antinflammtory drugs (NSAIDs) such as indometacin
Indometacin
Indometacin or indomethacin is a non-steroidal anti-inflammatory drug commonly used to reduce fever, pain, stiffness, and swelling. It works by inhibiting the production of prostaglandins, molecules known to cause these symptoms...
. It was developed in the 1980s as a new antiinflammatory and prostaglandin
Prostaglandin
A prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring....
synthesis inhibitor, acting through inhibition of the enzyme cyclooxygenase
Cyclooxygenase
Cyclooxygenase is an enzyme that is responsible for formation of important biological mediators called prostanoids, including prostaglandins, prostacyclin and thromboxane. Pharmacological inhibition of COX can provide relief from the symptoms of inflammation and pain...
(COX).
However pravadoline was found to exhibit unexpectedly strong analgesic effects, which appeared at doses ten times smaller than the effective anti-inflammatory dose and so could not be explained by its action as a COX inhibitor. These effects were not blocked by opioid antagonists
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
such as naloxone
Naloxone
Naloxone is an opioid antagonist drug developed by Sankyo in the 1960s. Naloxone is a drug used to counter the effects of opiate overdose, for example heroin or morphine overdose. Naloxone is specifically used to counteract life-threatening depression of the central nervous system and respiratory...
, and it was eventually discovered that pravadoline represented the first compound from a novel class of cannabinoid agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
s, the aminoalkylindoles.
Pravadoline was never developed for use as an analgesic, partly due to toxicity concerns (although these were later shown to be a result of the salt form that the drug had been prepared in rather than from the pravadoline itself), however the discovery of cannabinoid activity in this structurally novel family of drugs led to the discovery of several new cannabinoid agonists, including the drug WIN 55,212-2
WIN 55,212-2
WIN 55,212-2 is a chemical described as an aminoalkylindole derivative, that produces effects similar to those of cannabinoid derivatives such as THC but has an entirely different chemical structure....
which is now widely used in scientific research.
Animal studies
Administration of pravadoline on rats showed:- Prolonged the response latency induced by tail immersion in hot water at a temperature of 55 degrees Celsius (minimum effective dose, 100mg/kg s.c.)
- Prevented hyperalgesiaHyperalgesiaHyperalgesia is an increased sensitivity to pain, which may be caused by damage to nociceptors or peripheral nerves. Temporary increased sensitivity to pain also occurs as part of sickness behavior, the evolved response to infection.-Types:...
in rats with Brewer's Yeast injections during (Randall-Selitto testRandall-Selitto testThe Randall-Selitto test or paw pressure test is a technique for the measurement of the pain response in animals. It is used in basic pain research and to test the effectiveness of analgetics by observing the reaction to gradually increasing pressure on an inflamed paw...
) (minimum effective dose, 1mg/kg, p.o.) - Prevented the nociceptive response induced by paw flexion in the adjuvantAdjuvantAn adjuvant is a pharmacological or immunological agent that modifies the effect of other agents, such as a drug or vaccine, while having few if any direct effects when given by itself...
-arthritic rat (ED50,41mg/kg, p.o.) - Prevented the nociceptive response of bradykininBradykininBradykinin is a peptide that causes blood vessels to dilate , and therefore causes blood pressure to lower. A class of drugs called ACE inhibitors, which are used to lower blood pressure, increase bradykinin further lowering blood pressure...
-induced head and forepaw flexion (ED50, 78mg/kg, p.o.)
The antinociceptive activity of pravadoline cannot be explained by an opioid mechanism, because pravadoline-induced antinociception was not antagonized by naloxone (1mg/kg, s.c.) and pravadoline did not bind to the opioid receptor
Opioid receptor
Opioid receptors are a group of 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...
s at concentrations up to 10μM.
See also
- AM-630AM-630AM-630 is a drug which acts as a potent and selective inverse agonist for the cannabinoid receptor CB2, with a Ki of 32.1nM at CB2 and 165x selectivity over CB1, at which it acted as a weak partial agonist. It is used in the study of CB2 mediated responses and has been used to investigate the...
(6-iodopravadoline) - WIN 54,461WIN 54,461WIN 54,461 is a drug which acts as a potent and selective inverse agonist for the cannabinoid receptor CB2....
(6-bromopravadoline) - WIN 55,212-2WIN 55,212-2WIN 55,212-2 is a chemical described as an aminoalkylindole derivative, that produces effects similar to those of cannabinoid derivatives such as THC but has an entirely different chemical structure....
- RCS-4RCS-4RCS-4, or 1-pentyl-3-indole, is a synthetic cannabinoid drug sold under the names SR-19, BTM-4, or Eric-4 , but originally, OBT-199. As with all other research chemicals, human use is not encouraged or recommended...
(1-pentyl-3-(4-methoxybenzoyl)indole)