Thiorphan is the first potent synthetic inhibitor of enkephalinase. Thiorphan displays antinociceptive activity after systemic administration. Thiorphan also inhibits to a lesser extent the widely distributed angiotensin-converting enzyme, a carboxydipeptidase implicated in blood pressure regulation. Thiorphan failed to potentiate allergen-induced airway responses in asthma. Thiorphan significantly reduced the castor oil-induced diarrhea in rats when administered intravenously but not when administered intracerebroventricularly. Racecadotril, via its active metabolite thiorphan, was consistently effective in animal models and patients with various forms of acute diarrhea by inhibiting pathologic (but not basal) secretion from the gut without changing gastro-intestinal transit time or motility.

Metacetamol (3-hydroxyacetanilide) is a structural isomer of the widely used drug paracetamol and is being considered as a promising alternative to the latter because of its lower toxicity. 3-hydroxyacetanilide, the positional isomer of paracetamol, does not cause depletion of GSH in vivo or hepatotoxicity even though the extent of covalent binding of the reactive metabolite (in vivo or in vitro) is comparable to that for an equimolar dose of paracetamol. Metacetamol should prove to be a useful tool to aid in the discrimination of hepatic acetaminophen protein adducts that may be critical or noncritical to survival of hepatocytes

WS-12 is a cooling agent and potent TRPM8 agonist. It activates TRPM8 but not related TRP channels like TRPM3 and TRPV6. WS-12 seems to activate TRPM8 mediated cation currents by shifting the voltage dependence of the activation curves to the left toward more physiological membrane potentials. Highly selective TRPM8 activators may be useful for prostate cancer imaging and/or therapy and for therapy in chronic neuropathic pain states.

PF-06273340 is a brain penetrant, orally available and potent tropomyosin-related kinase (Trk) inhibitor. PF-06273340 has a low metabolic turnover in Human liver microsomes and hepatocytes is a good substrate for efflux transporters P-glycoprotein and Breast cancer resistance protein (BCRP) and have moderate passive permeability. PF-06273340 was investigated in Phase I clinical trials for the treatment acute and chronic pain. However clinical development has been discontinued.

URB-597 (KDS-4103) is a highly potent and selective inhibitor of the enzyme fatty acid amide hydrolase (FAAH), which catalyzes the intracellular hydrolysis of the endocannabinoid anandamide. URB597 is one the best studied carbamate-based inhibitors. Early studies showed that the compound did not inhibit or bind related biological targets. Administration of URB597 to rats and subsequent in vivo evaluation of brain FAAH activity showed the compound elevated endogenous anandamide levels. Importantly, the compound did not produce catalepsy, hypothermia, or hyperphagia, three of the typical effects of exogenous cannabinoids. The compound did produce antinociceptive effects in the mouse hot-plate test, which were reversed by the CB1 antagonist rimonabant. These findings again support the expectation that inhibition of FAAH produces pharmacology distinct from an exogenous CB1 agonist. A more detailed study was published later showing time-course data in mice demonstrating elevation of anandamide, oleamide, and N-palmitoyl ethanolamine for 2–6 h after administration of URB597. In vivo administration of URB597 showed almost complete inhibition of FAAH by the compound, and the FAAH inhibition was still approximately 70% after 16 h. Complete recovery of CNS FAAH activity was observed 24 h after administration of URB597. In vivo administration of URB597 or the cannabinoid receptor agonist HU210 reduced both mechanical allodynia and thermal hyperalgesia in the CFA model of inflammatory pain. Effects in the inflammatory model were partially reversed by CB1 and CB2 antagonists. In a related study, the compound produced analgesic effects in the mouse CCI model (neuropathic) when administered orally. These effects were also reversed by both CB1 and CB2 antagonists.

(R)-Norfluoxetine is a pharmacologically active metabolite of Fluoxetine that is a selective serotonin reuptake inhibitor. (R)-Norfluoxetine was being investigated by Eli Lilly and Company for treatment pain and drug abuse, but future development was discontinued.

Parafluorofentanyl is a selective mu-opioid agonist, an analog of fentanyl, developed by Janssen. The drug was not developed for human use but is produced and abused illegally.

Cizolirtine is a potent analgesic in mice and rats, with an efficacy superior to that of aspirin and other nonsteroid anti-inflammatory drugs. Recent studies have shown that the analgesic effect of cizolirtine could be related, at least partially, to an inhibition of spinal substance P and calcitonin gene-related peptide release. Cizolirtine has been in clinical trials for the treatment of pain and overactive bladder. Reported adverse events are: dry mouth, dizziness, nausea, vomiting, blurred vision.

Devazepide (L-364718 or MK-329) is a nonpeptide antagonist for the peripheral (type-A) cholecystokinin (CCK) receptor, which has proved effective in blocking the actions of both exogenous and endogenous CCK in several species. It is an orally active antagonist of CCK-stimulated pancreaticobiliary output in man. Devazepide has been developing for the treatment of anxiety, cancer, neuropathic pain however development discontinued.

HU-308 ([(1R,2R,5R)-2-[2,6-dimethoxy-4-(2-methyloctan-2-yl)phenyl]-7,7-dimethyl-4-bicyclo[3.1.1]hept-3-enyl]methanol) is a potent, selective agonist for the CB2 receptor. The synthesis and characterization took place in the laboratory of Prof. Mechoulam at the Hebrew University of Jerusalem in the late 1990s. It has analgesic effects, promotes proliferation of neural stem cells,[3] and protects both liver and blood vessel tissues against oxidative stress via inhibition of TNF-α. In vivo, HU-308 has hypotensive, analgesic, and anti-inflammatory activities in mice that can be reversed by the CB2 receptor antagonist SR 144528 but not the CB1 receptor antagonist rimonabant. Pretreatment of mice with HU-308 decreases the I/R-induced tissue damage, inflammatory cell infiltration, tissue, and serum TNF-α, MIP-1, and MIP-2 levels, tissue lipid peroxidation, and apoptosis. HU-308 increases proliferation of HT29 colon cancer cells and growth of tumors in an HT29 mouse xenograft model. The physiological and toxicological properties of this compound have not been evaluated in humans.