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.

Swainsonine is an indolizidine alkaloid found in Australian Swainsona canescens, North American plants of the genera Astragalus and Oxytropis and also in the fungus Rhizoctonia leguminocola. It is competitive inhibitor of Golgi alpha-mannosidase II and lysosomal alpha-mannosidases. This compound has been reported to be a potent antiproliferative and immunomodulatory agent. However, no evidence of anti-tumor activity of swainsonine was seen in phase II clinical trial, in patients with locally advanced or metastatic renal cell carcinoma. Adverse events such as fatigue, nausea and diarrhea were common but generally mild. Swainsonine is locoweed toxin. Locoweed poisoning is seen throughout the world and annually costs the livestock industry millions of dollars. Swainsonine inhibits lysosomal alpha-mannosidase and Golgi mannosidase II. Poisoned animals are lethargic, anorexic, emaciated, and have neurologic signs that range from subtle apprehension to seizures.

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.

Nemazoline (A-57219) is a nasal decongestant. It has alpha 1-agonist/alpha 2-antagonist activity and was more effective and long-acting than oxymetazoline on canine nasal mucosa, in-vitro and in-vivo. Upon intranasal administration to dogs, the compound was devoid of systemic effects up to a concentration 1000 times that needed for local decongestant effect (1.65 micrograms, atomized from a 1 microgram mL-1 solution) suggesting limited mucosal absorption. After nasal administration to rats for 15 days at a concentration 1000 times greater than that required for nasal decongestion, no mucosal tissue toxicity or systemic effects were seen.

Napitane [A 75200, ABT 200] is a norepinephrine uptake inhibitor and α2 adrenoceptor antagonist. It was undergoing clinical trials with Abbott in the USA as a treatment for depression. However it was discontinued later. Napitane is a potent alpha 2-adrenoceptor antagonist (Ki = 1.2 nM) with modest norepinephrine uptake-blocking activity (IC50 = 841 nM).

Atiprosin (AY-28,228), an octahydro-pyrazino-pyrido-indole drug, possesses the alpha-adrenoceptor antagonist activity and exerts antihypertensive effects. Atiprosin has never been marketed

Tiamenidine (also known as HOE 440) is a diazacycloalkene derivative patented by Farbwerke Hoechst A.-G. as 2 alpha-sympathomimetic antihypertensive agents. In preclinical models, tiamenidine induces hypotension and bradycardia in renal hypertensive cats and rats and in normal rats and dogs. Furthermore, Tiamenidine inhibits the liberation of norepinephrine from nerves leading to the heart and suppress sympathetic circulatory reflexes in dogs. In clinical trials, Tiamenidine exerts favor influences on systolic and diastolic blood pressure, and reduces plasma noradrenaline and adrenaline levels and suppresses plasma renin activity. Unfortunately, during the withdrawal of Tiamenidine, there is a rebound of blood pressure and plasma noradrenaline and adrenaline, overshooting baseline levels.

Napamezole [WIN 51181] is a potent alpha-2 adrenergic receptor antagonist and a selective inhibitor of 5-hydroxytryptamine re-uptake in vitro. Napamezole was at the phase I stage of development with Sanofi Winthrop (formerly known as Sterling Drug before it was purchased by Sanofi) in the USA as a treatment for depression. The alpha adrenergic antagonist activity of napamezole was determined in vitro in rat brain receptor binding assay using [3H]clonidine and [3H]prazosin for alpha-2 and alpha-1 receptors, respectively. The Ki values for napamezole were 28 nM (alpha-2) and 93 nM (alpha-1).