Prothixene is a thioxanthene derivative patented by Swiss multinational healthcare F. Hoffmann-La Roche & Co. as an antiemetic and neuroleptic agent. In preclinical models, prothixene shows patent antihistaminic activity. The central depressant activity of prothixene in the rotating rod test and the potentiation of thiopental narcosis and hypothermia in white mice (H strain) is one order lower than in the case of chlorprothixene. Prothixene has a higher protective effect in the supramaximal electric shock test with mice than promethazine and chlorprothixene. However, it has no effect on the reserpine ptosis in mice nor on the ulcerogenic action of reserpine in rats (Wistar strain). Its anti-serotonin activity is higher in vivo and in vitro than that of promethazine. The local irritation, tested on rabbits, is lower by 52% after prothixene application than after promethazine. Prothixene applied parenterally is more toxic to mice than promethazine. In oral administration, to mice, no differences in toxicity were found.

Proxicromil is substituted chromone patented in the late 1970s by Fisons Ltd. for the treatment of allergic asthma. Proxicromil acts on to FcεRIreceptor in mast cells, thereby inhibiting the production of histamines. Proxicromil is tested through a variety of independent studies for its beneficial effect as an anti-allergen, its efficacy against migraine, asthma and tumor enhancement. It shows no effect as a prophylactic against migraine. The reported side effects during this study related mainly to transient gastrointestinal troubles and were generally of a mild nature. For asthma and exercise-induced bronchospasm, Proxicromil was found to be mildly effective. But the investigation was discontinued when malignancies occurred in long-term animal studies.

Decloxizine (UCB-1402; NSC289116) is a histamine 1 receptor antagonist. Decloxizine is a broncholyticum.

Nuvenzepine is an mAChR antagonist previously in phase I clinical trials for the treatment of gastrospasm. Nuvenzepine substantially shares the antimuscarinic properties of pirenzepine but it is also endowed with a (weak) H1-blocking action. Nuvenzepine is selective for M1 receptors (pA2 = 6.63-7.74). Nuvenzepine, administered intraduodenally, displayed a long-lasting and dose-dependent inhibition of neostigmine-induced intestinal motility in anaesthetized cats. On ileal motor activity, the compound showed a potency 10 times greater than that of pirenzepine, and, although to a lesser extent, it was also active, unlike pirenzepine, on colonic stimulated motility. In conscious cats, nuvenzepine inhibited pentagastrin-stimulated gastric acid secretion resulting 25-30 times more potent than pirenzepine.

Telenzepine is a selective muscarinic M1 receptor antagonist that was studied for selective inhibition of gastric acid secretion. Telenzepine was used in clinical trials in patients with acute duodenal ulcer, where was found that once daily administration of 3 mg in the evening must be regarded as the optimal dosage regimen of telenzepine. However, the preregistration for peptic ulcer in Germany was discontinued. In addition, the drug was studied in patients with nocturnal asthma. It was shown that telenzepine via the oral route at a dose of up to 5 mg was not effective in preventing nocturnal asthma.

Telcagepant (MK-0974) is a calcitonin gene-related peptide receptor antagonist. Merck & Co was developing telcagepant for the treatment of pain. Telcagepant is an extremely potent CGRP antagonist with a Ki = 0.77 (0.07 nM). Telcagepant showed efficacy against acute migraines; however, different patient populations may show more beneficial effects with telcagepant versus triptans. In the acute treatment of migraine, Telcagepant was found to have equal potency to rizatriptan and zolmitriptan in two Phase III clinical trials. Merck & Co has now terminated development of the drug.

Clorotepine (aka octoclothepin or octoclothepine) is an antipsychotic from the tricyclic group derived from perathiepin. It was originally developed in 1965 and marketed in the Czech Republic by Spofa in or around 1971 for the treatment of schizophrenic psychosis. Clorotepine has a high affinity for the dopamine (D1, D2, D3, D4), receptors the serotonin 5-HT (2A, 2B, 2C, 6, 7) receptors, the alpha-adrenergic receptors (1A, 1B, 1D), and the histamine H1 receptors. In most instances, it acts as an antagonist (or inverse agonist). Clorotepine will also block the reuptake of norepinephrine by inhibiting the norepinephrine transporter.

Zaprinast is (M&B 22,948; 2-o-propoxy-phenyl-8-azapurin-6-one) is a selective inhibitor of cyclic GMP (cGMP)-dependent phosphodiesterases, with vasodilation activity in a variety of species and tissues. The potency of zaprinast as a vasorelaxant varies with the species, the tissue, and the presence and absence of endothelium. Zaprinast apparently loses all or most of its vasorelaxant capacity when arteries have been denuded of the endothelial cell layer. Alternatively, the vasorelaxant effects of zaprinast can be attenuated using methylene blue, an inhibitor of soluble guanylate cyclase and hemoglobin inhibitor of nitric oxide synthesis. Therefore, zaprinast-induced relaxations appear to be endothelium-dependent. In human platelets zaprinast, at a dose of 10 mkM, caused a modest (20%) inhibition of aggregation as well as a small increase in cGMP content. In anesthetized rats, zaprinast dose-dependently lowered mean arterial blood pressure (MAP), an effect that correlated well with increased levels of plasma cGMP. Zaprinast decreased mean arterial pressure, the reduction being inversely related to zaprinast concentration. Zaprinast had no effect on heart rate, but increased cardiac output, urinary output, urinary sodium excretion, as well as renal blood flow. Oral administration of zaprinast to spontaneously hypertensive rats at a dose of 200 mg/kg/day normalized blood pressure. In normotensive rats, however, no changes in blood pressure were observed with the same treatment. In an initial placebo-controlled, double-blind crossover trial, 10 mg of zaprinast was effective in reducing exercise-, but not histamine-induced bronchoconstriction in adult asthmatics. However, in a similar study with asthmatic children, zaprinast was ineffective in preventing exercise-induced bronchoconstriction. Since then the clinical development of zaprinast has been discontinued.

Omigapil (CGP 3466 or TCH346) is a structurally related analog of R-(-)-deprenyl that exhibits virtually no monoamine oxidase type B inhibiting activity but is neuroprotective in the picomolar concentration range. It binds to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and at subnanomolar concentrations prevent the S-nitrosylation of GAPDH, inhibit GAPDH-Siah binding and prevent the nuclear translocation of GAPDH. Omigapil demonstrated promising potential in the treatment of Parkinson's disease and motoneuron disease in animal models, however, it did not show efficacy in clinical trials. Omigapil is in development for the treatment of congenital muscular dystrophy.

Mitoquidone is pentacyclic pyrroloquinone derivative developed for clinical evaluation as a potential anticancer agent. Mitoquidone demonstrated good activity in a range of experimental solid tumour models, but was weakly active against standard prescreens such as the P388 murine leukaemia. Bone marrow suppression or other significant toxicity was not observed in preclinical studies. In clinical trials patients were treated with Mitoquidone given as a 4-h infusion either once every 21 days, once a week, or as 5 daily doses repeated every 28 days. The major adverse events encountered included nausea and vomiting (in virtually all patients), dyspnoea, tumour-related pain, and thrombocytopenia in several patients with pretreatment bone-marrow impairment. Phase I studies were suspended without a maximum tolerated dose being reached because of formulation difficulties. There were no major responses, although stable disease was observed in a number of patients with gastrointestinal malignancies.