Pyrroliphene is a dialkylaminodiphenylbutanol ester with antitussive and analgesic activities. In clinical trials the major side effect of Pyrroliphene was sedation, and the other side effect liabilities were similar to those of morphine.

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.

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.

Phencyclidine is an illegal, hallucinogenic drug that was initially used as an anesthetic agent in the 1950s and early 1960s, but was then withdrawn in 1965 because of dissociative hallucinogenic effects that were often disturbing and sometimes severe and prolonged. Phencyclidine is a noncompetitive NMDA (N-methyl-D-aspartate) receptor antagonist and glutamate receptor antagonist, but also interacts with other receptor sites, and may have effects with dopamine, opioid and nicotinic receptors. Phencyclidine disrupts the functioning of receptors for the neurotransmitter glutamate, which plays a major role in the perception of pain as well as in learning, memory, and emotion. It also influences the actions of the neurotransmitter dopamine, which causes the euphoria associated with drug use. Phencyclidine overdose deaths may occur after taking a large dose, though many phencyclidine related deaths result from delusions and other psychological consequences of the drug’s use. There have been reports of death due to accidental drowning, leaping from high places, and motor vehicle accidents in addition to violent episodes of self-mutilation, suicides, and homicides.

Cinanserin is a 5-hydroxytryptamine receptor antagonist; it shows a low affinity to 5-HT2b binding sites and a 4-to 10-fold lower affinity to 5-HT2c receptor binding sites than for 5-HT2a sites. Nevertheless, at concentrations normally used 5-HT2c receptor blocking effects are still likely. Experiments on animal have shown that intravenous administration of cinanserin significantly reduces systemic burn edema and leukocyte-endothelial interactions.

Cetamolol is a beta adrenergic antagonist with intrinsic sympathomimetic activity, patented by Imperial Chemical Industries Ltd for cardiovascular disease treatment. The average plasma half-life of cetamolol is 6.4 hours in humans and peak serum levels are reached 1 to 2 hours after drug intake; oral doses as low as 10 mg produced significant reductions in exercise-induced tachycardia 24 hours after drug administration. Cetamolol is approximately three times as potent as atenolol in blocking exercise-induced tachycardia.

Proxorphan is a N-substituted 6-oxamorphinane patented by American pharmaceutical company Bristol-Myers Co. as opioid analgesic and antitussive drug. Proxorphan acts as a κ-opioid receptor partial agonist and to a lesser extent as a μ-opioid receptor partial agonist.

Zenazocine is an opioid analgesic that mixes both agonist/antagonist activities. This compound participated in phase II clinical trial, however, the further development was ultimately halted and it has never been marketed.

Nafimidone is a candidate anticonvulsant agent. The anticonvulsant effectiveness of nafimidone was evaluated in the kindled amygdaloid seizure model in rats. Nafimidone (25-50 mg/kg) significantly reduced supranthreshold elicited afterdischarge length and seizure severity only at doses with some prestimulation toxicity. The maximum anticonvulsant effectiveness for the 25 mg/kg i.p. dose of nafimidone was seen between 15 and 30 min utilizing a suprathreshold kindling paradigm. Nafimidone did not significantly elevate seizure thresholds at the doses tested; however, nafimidone (3.1-50 mg/kg) reduced the severity and afterdischarge duration of threshold elicited seizures in a non-dose response manner. Nafimidone is a new antiepileptic drug which may be effective in partial onset seizures in humans.

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).