LY2300559 is a dual metabotropic glutamate receptor 2 (mGluR2) positive allosteric modulator and cysteinyl leukotriene receptor 1 (CysLTR1) antagonist. Eli Lilly was developing LY2300559 for the prevention of migraine. LY2300559 development has been discontinued.

Otenzepad is the first competitive muscarinic M2 antagonist that is cardioselective and had been in phase III clinical trials for the treatment of arrhythmias and bradycardia. Otenzepad was originally developed by Boehringer Ingelheim Pharma KG (Boehringer Ingelheim) in Germany. The parent company is developing oral and IV formulations of the drug for use in symptomatic bradycardia, sinus bradycardia, sick sinus syndrome and symptomatic arrhythmias after intoxication. However, all these research has been discontinued. Otenzepad binds to muscarinic cholinergic receptors in a simple competitive manner. Its affinity for cardiac (M2) muscarinic receptors is about 7 times greater than for ganglionic (M1) receptors and about 36 times greater than for glandular (M3) receptors. The (+)-enantiomer of otenzepad is about 8 times more potent at M2-receptors than the (−)-enantiomer. In a double-blind study, 48 healthy male volunteers were randomised to single oral doses of placebo or otenzepad (120, 240 or 480mg). Heart-rate (HR) was significantly increased by the 250 and 480mg doses (by 15 and 21 beats/minute, respectively). The 480mg dose also increased Diastolic Blood Pressure (DBP) significantly compared with placebo. The oral pharmacokinetics of otenzepad were investigated in a double-blind study in which 48 healthy male volunteers were randomised to single oral doses of placebo or otenzepad (120, 240 or 480mg). Otenzepad bioavailability was 45%, mean residence time (MRT) was 12.5 hours and tmax occurred 2.5 hours postdose.

PF-3274167 (Cligosiban) is a potent, selective, brain penetrant oxytocin receptor antagonist. Cligosiban interrupts the expulsion phase of ejaculation by reducing the normal bulbospongiosum burst pattern and reducing the expulsions that accompany bursts. Cligosiban represents a promising compound to test the clinical hypothesis that antagonism of central oxytocin receptors may be of therapeutic benefit in the treatment of premature ejaculation. [11C]PF-3274167 is not a suitable tracer for imaging of OTR in rat brain, probably because of a too low affinity for this receptor in addition to a poor brain penetration. PF-3274167 had been in phase I clinical trial for the treatment of sexual function disorders and urinary incontinence. However, this research has been discontinued.

Taladegib (LY2940680) is an orally bioavailable small molecule antagonist of the Hedgehog (Hh)-ligand cell surface receptor smoothened (Smo) with potential antineoplastic activity. Taladegib inhibits signaling that is mediated by the Hh pathway protein Smo, which may result in a suppression of the Hh signaling pathway and may lead to the inhibition of the proliferation of tumor cells in which this pathway is abnormally activated. The Hh signaling pathway plays an important role in cellular growth, differentiation and repair; constitutive activation of this pathway is associated with uncontrolled cellular proliferation and has been observed in a variety of cancers. Taladegib has excellent pharmacokinetic properties in rodent and non-rodent species. Taladegib administrated orally treats Ptch+/- p53-/- transgenic mice which spontaneously develop medulloblastoma, produces remarkable efficacy and significantly improves their survival. Taladegib reveals rapid kinetics of anti-tumor activity through magnetic resonance imaging of these mice, and Taladegib induces Caspase-3 activity and reduces proliferation by immunohistochemistry analysis of medulloblastoma tumors. Taladegib inhibits Hh regulated gene expression in the subcutaneous xenograft tumor stroma and produces significant anti-tumor activity. Taladegib is currently in phase I clinical trials for ovarian cancer and solid tumours and in phase I/II for esophageal cancer. Ignyta exclusively licensed Taladegib from Eli Lilly and Company in November 2015.

Enerisant is a histamine H3 receptor antagonist. In H3 receptor binding assay using (R)​-​α-​methyl[3H]​histamine, enerisant showed IC50 of 4.9 nM. Enerisant may be useful for the treatment of Alzheimer's disease, schizophrenia, etc.

JNJ-39758979 is a histamine H4 receptor antagonist which clinical development for asthma and atopic dermatitis was halted during phase II because of the observation of idiosyncratic drug-induced agranulocytosis in two subjects.

Rolofylline is an adenosine A1-receptor antagonist. Plasma adenosine levels are elevated in patients with heart failure and adenosine A1 receptors in the kidney mediate vasoconstriction of afferent arterioles, reabsorption of sodium and water in proximal tubules, and tubuloglomerular feedback in the juxtaglomerular apparatus. Accordingly, inhibition of these receptors would be expected to increase renal blood flow and enhance diuresis. However, rolofylline showed no difference from placebo in the main efficacy end points in Phase III clinical trials for acute heart-failure patients.

(±)-quinuclidinyl benzilate (3-quinuclidinyl benzilate), is a specific muscarinic cholinergic receptor antagonist. It binds potently but reversibly to the muscarinic cholinergic receptors of mammalian brain and peripheral tissues. 3-quinuclidinyl benzilate was invented by Hoffmann-La Roche Inc in 1951, while investigating antispasmodic agents resembling tropine for the treatment of gastrointestinal conditions. In the 1960s 3-quinuclidinyl benzilate, was developed and weaponized as a new chemical agent for battlefield use as a psychochemical. Assigned the NATO code BZ it is classified as a hallucinogenic chemical warfare agent that affects both the peripheral and central nervous systems (CNS). It is one of the most potent anticholinergic psychomimetics known, with only small doses necessary to produce incapacitation. The primary route of absorption is through the respiratory system but absorption also can occur through the skin or gastrointestinal tract. BZ is odorless and is usually disseminated as an aerosol. Data regarding the health effects of BZ in humans following inhalation exposure are limited to military application studies. Pharmacologic activity of 3-quinuclidinyl benzilate is similar to other anticholinergic drugs (eg, atropine) but with a much longer duration of action. It was shown that I[3H]-3-quinuclidinyl benzilate accumulated in various brain regions after intravenous injection. The specific binding of [3-3H]3-quinuclidinyl-benzilate and [125I]3-quinuclidinyl-(3-iodo-4-hydroxy-benzilate) to rat brain subcellular fractions is parallel in myelin, synaptic plasma membrane and mitochondrial fractions with a 3-4-fold enrichment observed in synaptic plasma membrane over crude mitochondrial fractions. These findings suggested the use of 3-quinuclidinyl benzilate as a binding probe useful in assaying low levels of muscarinic receptor in tissue culture and other biological sources including labeling the receptor in vivo for autoradiographic studies. M2 muscarinic acetylcholine receptor (M2 receptor), essential for the physiologic control of cardiovascular function through activation of G protein-coupled inwardly-rectifying potassium channels, was shown to bind 3-quinuclidinyl benzilate with high affinity in vitro.