Cicaprost is a prostacyclin receptor (IP) agonist and orally active prostacyclin analog with potent systemic and pulmonary vasodilatation and anti-inflammatory activity. In preclinical models, Cicaprost treatment largely prevented the hypercholesterolemia-related impairment of coronary vasodilation and nitric oxide release in Isolated Langendorff-hearts. Cicaprost inhibits proinflammatory chemokines production not only from lipopolysaccharides (LPS) or (tumor necrosis factor-alpha) induced primary human monocyte-derived macrophages but also from LPS-stimulated monocyte-derived dendritic cells. Besides that Cicapost strongly inhibits lymph node and organ metastases of spontaneously metastasizing mammary tumors with a mode of action different from cytostatic or antihormonal drugs. In animal models, Cicaprost prevents metastasis if given continuously from the day of tumor implantation, and is effective in reducing metastasis if treatment is begun following surgical removal of the primary tumor when micrometastases are already present. Clinical trials of Cicaprost in healthy male volunteers demonstrate significant anti-platelet and vasodilatory effects.

Cimaterol is a chemically stable nonselective agonist β1-, β2-, and β3-adrenoceptors. Cimaterol is used in sport as a stimulant and a fat burner that assists bodybuilders and strength athletes to get rid of body fats. Aside from shedding off fats, another benefit for using cimaterol for athletes is a boost in strength as well as an increase in muscle size or lean body mass. The increase in muscle size has been seen in previous animal studies when cimaterol is used. However, the reason behind the muscle gain is not identified yet, but the body has a very different response compared from taking in anabolic steroids. Experts in the field are saying that the increased nitrogen retention, that is known to cause by cimaterol, maybe the reason behind the muscle gain. Another great thing about Cimaterol is that, it can improve blood flow.

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.

Colterol is a beta-2 adrenoreceptor agonist. Bitolterol, a diester prodrug of colterol, was marketed by Elan Pharmaceuticals for the treatment of reversible bronchospasm associated with asthma or chronic obstructive pulmonary diseases.

Pardoprunox is a partial D2/3 dopamine receptor agonist and full 5-HT1A serotonin receptor agonist. Partial D(2/3) dopamine (DA) receptor agonists provide a novel approach to the treatment of the motor symptoms of Parkinson's disease that may avoid common dopaminergic side effects, including dyskinesia and psychosis. Pardoprunox passed phase III clinical trial for the treatment of Parkinson's disease.

Pumosetrag is a novel, orally active and selective 5-HT 3 agonist. It is a partial agonist in rats and guinea-pig and a full agonist in the mouse, suggesting important species differences in 5-HT3 receptor structure. Pumosetrag had been in phase II clinical trials for the treatment of gastroesophageal reflux disease and irritable bowel syndrome. No serious adverse events were reported. Diarrhea was not more common on the drug and only one subject experienced pruritus. All researches on this drug candidate are discontinued.

Ragaglitazar (DRF 2725, NNC 61-0029) is phenoxazine analog of phenyl propanoic acid having dual (PPARα and PPARγ) agonist property intended to restore insulin sensitivity and correct diabetic dyslipidemia. PPAR-α is highly expressed in liver and muscle and upon activation leads to decreases in plasma triglycerides and increases in HDL cholesterol levels. PPAR-γ activation leads to enhancement of glucose uptake in skeletal muscles and adipose tissue. Ragaglitazar provided the glycemic control that was comparable with that of pioglitazone and, compared with placebo, provided a significant improvement in the lipid profile.

Tecalcet (also known as KRN-568; NPS-R-568; R-568), is an oral calcium channel agonist potentially for the treatment of hyperparathyroidism. Calcimimetics, such as Tecalcet, are agonists and activate the calcium channel in a non-competitive fashion. Tecalcet does not compete directly with calcium that activates the receptor through binding in the extracellular domain of these receptors, but rather, calcimimetics such as Tecalcet, bind allosterically in the seven transmembranes to ‘sensitize’ the receptor to extracellular calcium. Tecalcet acts as an agonist of the calcium receptors of the parathyroid cells, causing a decrease in PTH release. Tecalcet also acts on the parafollicular cells (C-cells) of the thyroid gland, resulting in an increase in calcitonin release. These effects ultimately lead to a decrease in plasma calcium concentrations. Studies in rats have shown that oral administration of R-568 at doses ranging from 3 to 100 mg/kg caused a rapid (<30 minutes) decrease in plasma PTH concentrations and an increase in calcitonin concentrations, accompanied by a dose-dependent decrease in calcium concentrations. Tecalcet had been in phase II clinical trials by for the treatment of hyperparathyroidism, postmenopausal osteoporosis and rheumatic disorders in Japan and US. Development of Tecalcet has been discontinued.

Fadolmidine (MPV 2426) is an alpha2-adrenoceptor agonist. Fadolmidine displayed high affinity and full agonist efficacy at all three human alpha2-adrenoceptor subtypes (A, B and C). Various preclinical models of pain have been employed and have demonstrated fadolmidine potential as an analgesic, including its potential for use in neuropathies and post-operative pain. A Phase II clinical trial successfully demonstrated that intrathecal fadolmidine, in combination with bupivacaine, produced analgesic effects compared to bupivacaine alone in bunionectomy patients.

Evatanepag (CP-533,536) is a prostaglandin E2 EP2 receptor agonist. It stimulates new bone formation on trabecular, endocortical, and periosteal surfaces and enhances fracture healing. Evatanepag was under development with Pfizer as a bone formation stimulant for therapeutic use in the healing of fractures.