Tetrazolast (also known as MDL 26,024GO) is a tetrazoloquinoline derivative patented by Merrell Dow Pharmaceuticals, Inc. as an antiallergic and antiasthmatic agent. Tetrazolast was shown to be an orally absorbed mediator release inhibitor in the rat passive cutaneous anaphylaxis and passive peritoneal anaphylaxis tests. In addition, the compound was shown to both elicit and inhibit elicitation of the Bezold-Jarisch reflex in the dog. Tetrazolast also significantly reduced Ascaris-induced changes in pulmonary mechanics in cynomolgus monkeys. The compound inhibited both early and late phase antigen induced-changes in Ascaris-sensitive sheep, as well as the increased airway hyperreactivity which normally follows antigen challenge.

Risotilide is a Class III antiarrhythmic agent that inhibits the voltage-dependent potassium channel. Risotilide prolongs cardiac action potentials and refractory periods. It was shown to reduce ventricular vulnerability in a study on arrhythmogenic effects of left ventricular hypertrophy (LVH) in the intact heart in cats. Phase I and II trials have been conducted, but development of this drug has been discontinued.

Sergolexole [LY 281067] is an ergoline ester similar in structure to amesergide [LY 237733], with potent and highly selective antagonist activity at serotonin 2. The preclinical pharmacologic activity of LY 281067 shows it to be a potent and highly selective serotonergic (5-HT2) receptor antagonist. Based upon binding studies with 5-HT2 receptors in brain cortical membranes and block of 5-HT-induced contractions in the rat jugular vein, LY 281067 showed high affinity at 5-HT2 receptors with a dissociation constant of approximately 1 nM. LY 281067 was a highly selective 5-HT2 receptor antagonist without appreciably binding to 5-HT1, D1 or D2 receptors or interacting with histamine (H1), cholinergic, beta adrenergic or alpha-1 adrenergic receptors in smooth muscle. LY 281067 had modest affinity at alpha-2 receptors with a dissociation constant of approximately 100 nM. Oral bioavailability of LY 281067 in spontaneously hypertensive rats was excellent with an oral to i.v. dose ratio approximating 4. Sergolexole was undergoing phase II clinical trials with Eli Lilly in the USA as a potential treatment for migraine and anxiety, but development of this compound, but development of this compound has been discontinued.

Renzapride (BRL-24924) is a mixed 5-hydroxytryptamine type 4 (5-HT4) agonist and 5-HT3 receptor antagonist. This compound has a stimulatory effect on gastrointestinal motility and transit. Renzapride has been evaluated for use in treatment of irritable bowel syndrome (IBS). Data also suggested a potentially beneficial effect on abdominal pain/discomfort in women with constipation-predominant irritable bowel syndrome. Phase III clinical trials investigated if this drug could help alleviate the symptoms associated with this type of IBS. However, one phase III study has been terminated due to inefficient efficacy (compared to placebo).

Plomestane is an enzyme-activated aromatase inhibitor. Plomestane have demonstrated their ability to irreversibly inhibit estrogen biosynthesis in human placental microsomes. Plomestane have a dose-dependent effect on the metabolism of androstenedione in vitro in human breast tissues. It is selective inhibitors of aromatization in human breast tissues and may provide a mechanism for controlling estrogen responsive processes. Prolonged administration of plomestane to rats bearing dimethylbenzanthracene-induced mammary tumors resulted in significant regression of hormone-responsive tumors within several days. In animal models, the effects of plomestane on both regression of existing tumors and the appearance of new tumors were reversed by co-administration of estradiol. Thus, plomestane impairs estrogen-dependent mammary tumor growth, resulting in cessation of new growth and regression of responsive tumors.

Mergocriptine (2-methyl-a-ergocryptine or CBM36-733) is a synthetic long-acting ergot derivative. It exerts agonistic action at dopamine receptors. Mergocryptine may induce the suppression of striatal dopamine turnover by reducing dopamine release via the stimulation of presynaptic dopaminergic autoreceptors. In animal experiments, it may affect cerebral hemodynamics. Mergocriptine has a protective effect on the brain against ischemia.

Nornicotine is a natural alkaloid produced by plants in the genus Nicotiana and is structurally related to nicotine. Nornicotine is the direct precursor of tobacco-specific nitrosamine N'-nitrosonornicotine, which is a highly potent human carcinogen. Nornicotine is an active nicotine metabolite, which accumulates in brain to pharmacologically relevant concentrations following repeated nicotine administration to rats. Nornicotine stimulated DA release from nucleus accumbens in a nicotinic receptor-mediated manner, further supporting the hypothesis that nornicotine contributes to tobacco dependence. Nornicotine is present in Nicotiana tobaccum in both S(-) and R(+) enantiomeric forms. Nornicotine enantiomeric forms appear to differ in analgesic potency and side effects. Exposure to nornicotine results in additional activation of α7-type receptors, which may be important for effects on cognition and attention. Likewise, the effects of nornicotine on α6-containing receptors may contribute to the reinforcing effects of nicotine, and therefore, is relevant to dependence on tobacco. In contrast to nicotine, nornicotine had relatively low activity on receptors other than those containing α7 or α6 subunits. Yaupon Therapeutics was developing Nornicotine as a once a day oral drug for smoking cessation. However this development was discontinued.

Ioflubenzamide I-131 (also known as 131-I-MIP-1145) is a radiolabeled iodobenzamide derivative developed by Molecular Insight Pharmaceuticals, Inc for metastatic melanoma treatment. The benzamide moiety of Ioflubenzamide I-131 binds to melanin, selectively delivering a cytotoxic dose of gamma and beta radiation to melanin-expressing tumor cells. In human melanoma xenografts, Ioflubenzamide I-131 exhibited diffuse tissue distribution and washout from all tissues except melanin-expressing tumors. The administration of Ioflubenzamide I-131 at 25 MBq in single or multiple doses significantly reduced SK-MEL-3 tumor growth, with multiple doses resulting in tumor regression and durable response for over 125 days. Unfortunately Phase I clinical trial was terminated by unknown reason.

Tocofibrate is a peroxisomotropic ester compound consisting of both clofibric acid and alpha-tocopherol. Tocofibrate is a hypocholesterolemic drug. Lowering activity of tocofibrate in cholesterol level in blood was no less than that of clofibrate in rats fed high-fat cholesterol diet. In view of the fact that only a fraction of tocofibrate is not hydrolyzed in the liver 24-hr following oral administration, it was reasonable to assume that tocofibrate exerts its effect in an unaltered state rather than as a result of hydrolysis to clofibric acid and alpha-tocopherol. The distribution of tocofibrate clearly differs from that of both clofibrate and alpha-tocofibrate is primarily associated with its effect upon liver peroxisomes. Tocofibrate acts upon peroxisomes to lower plasma lipid levels.

Tosifen was synthesized originally in a series of compounds whose basic structural moiety, the sulfonyl urea nucleus, was of interest for potential hypoglycemic action. But tosifen is only a weak hypoglycemic agent. It is a potential antianginal and antiarrhythmic agent. The duration of action of tosifen was considerably longer than nitroglycerin and its lack of side effects considerably greater than propranolol. No long-term harmful effects have been observed during 13-week toxicity studies in animals. Tosifen differed from standard antianginal agents which may act via beta-adrenergic blocking activity or alteration of cardiac or circulatory dynamics since no acute pharmacological changes were observed after tosifen was administered. Tosifen was readily absorbed in both rats and dogs. The rates of absorption, metabolism, and urinary excretion were higher in the rat than in the dog.