Mezilamine is a dopamine antagonist, it blocks presynaptic but stimulates postsynaptic alpha-adrenoceptors. Potential antipsychotic drug.

Enclomiphene (Androxal), in development by Repros Therapeutics Inc, is a non-steroidal estrogen receptor antagonist that promotes gonadotropin-dependent testosterone secretion by the testes. Enclomiphene constitutes the trans-stereoisomer of clomiphene citrate, a drug that has been widely prescribed for several decades for the treatment of female ovulatory dysfunction. Because of the antagonistic effects of enclomiphene, the drug has the potential to increase serum testosterone levels in men with secondary hypogonadism by restoring physiological endogenous testosterone secretion while maintaining testicular volume and, potentially, spermatogenesis. In clinical trials conducted to date, enclomiphene demonstrated significant efficacy in the physiological restoration of testosterone levels in males with secondary hypogonadism. The compound also exhibited an unanticipated favorable effect on fasting plasma glucose; this result has been accompanied by rapidly accumulating evidence from other researchers for a bidirectional relationship between low serum testosterone and obesity/metabolic syndrome (syndrome X) in men.

RGH-896 (radiprodi) is orally active and selective NMDA NR2B antagonist, a potential therapeutic agent in treatment of neuropathic pain and possibly other chronic pain conditions. It blocks pain signaling without interacting with other NMDA receptor subtypes thus potentially improving therapeutic index and side effect profile. RGH-896 is the first of this group and is currently in early clinical development. Forest and Richter initiated a Phase IIb study in neuropathic pain in the United Stated in the second half of 2006. The drug did not produce significant reductions in patient-reported pain scores for all the dosages tested. Forest says that it and Gedeon Richter will review the findings before making a decision about the further development of radiprodil. In addition to neuropathic pain, the companies intend to investigate various other pain conditions and possibly CNS indications not related to pain. Forest will pay Richter undisclosed upfront and milestone payments in addition to royalties and will have exclusive rights in the U.S. and Canada. The two companies will jointly fund the development program. RGH-896 has patent applications that provide patent protection until at least 2022.

ZK 200775, also known as fanapanel, an antagonist at the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor, possesses neuroprotective efficacy in patients with acute ischemic stroke. However, the phase II of clinical trials had revealed, that this compound had led to the neuronal dysfunction and the glial cell toxicity had occurred. In addition, was shown, that the antagonization of AMPA receptors by ZK200775 lead to alterations of color and dark vision, visual acuity, cone electroretinogram (ERG) modalities and the pattern-reversal visual evoked potentials and to a lesser extent on the scotopic ERG. At the same time, ZK 200775 did not alter eye morphology, the functioning of the extraocular muscles, binocular vision, visual fields or the pupil.

Enrasentan is an orally active mixed endothelin A/B receptor antagonist with a 100-fold greater affinity for the endothelin A receptor. In an animal model of hypertension and cardiac hypertrophy the drug has reduced blood pressure, prevented cardiac hypertrophy and preserved myocardial function. In rats with hyperinsulinemia and hypertension enrasentan normalized blood pressure and prevented cardiac and renal damage. In rats with stroke the drug reduced the ischemic area in the brain. Enrasentan had been in phase II clinical trial for the treatment of heart failure but the results suggested that enrasentan does not appear to have favorable effects on ventricular remodeling.

Cenicriviroc (also referred to as TBR-652 and TAK-652) is an orally active, potent inhibitor of ligand binding to C-C chemokine receptor type 2 (CCR2) and C-C chemokine receptor type 5 (CCR5). Cenicriviroc does not inhibit ligand binding to CCR1 (an alternative target of CCR5 ligands). The mean half-life in healthy volunteers is 35 to 40 hours, which allows daily dosing of the drug. Due to its CCR5 blocking activity, Cenicriviroc has initially been tested as a drug against CCR5-tropic HIV infection. In a double-blind placebo-controlled trial involving 54 HIV infected participants, Cenicriviroc monotherapy at different doses (25, 50, 75, 100, or 150 mg) led to a dose-dependent reduction in HIV-1 RNA levels and concomitant increases in circulating levels of the CCR2 ligand monocyte chemoattractant protein 1 (MCP-1, or CCL2), suggesting potent CCR2 and CCR5 inhibition in vivo. According to clinical trials, Cenicriviroc is a very safe drug with a wide therapeutic range and fairly low pharmacokinetic variability. In animal models of liver diseases, Cenicriviroc potently inhibits macrophage accumulation in the liver and ameliorates fibrosis. In a phase 2b clinical trial on 289 patients with NASH and fibrosis, Cenicriviroc consistently demonstrated liver fibrosis improvement after 1 year of therapy and had an excellent safety profile.

Ruzadolane (previously known as UP 26-91) is a serotonin receptor antagonist that was developed as a non-narcotic, centrally acting analgesic agent for the treatment of anxiety disorder and pain. However, these studies were discontinued.

Indantadol (previously known as CHF-3381) is an oral and noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist and reversible monoamine oxidase-A (MAO-A) inhibitor that is being developed by Vernalis plc, under license from Chiesi Farmaceutici SpA, for the potential treatment of neuropathic pain. In preclinical studies, indantadol exhibited neuroprotective effects after kainate-induced seizures and displayed anticonvulsant and antihyperalgesic activity. Indantadol also caused a dose-dependent decrease in exploratory motility. In a human heat-capsaicin-induced pain model, indantadol at a dose of 500 mg effectively reduced the area of secondary hyperalgesia. The tolerability profile of the drug at single doses up to 600 mg and twice-daily doses up to 400 mg in clinical trials was significantly more favorable than for other NMDA antagonists. Most side effects have been observed to be mild, and include dizziness and asthenia. Indantadol was in phase II clinical trials for the treatment of chronic cough and neuropathic pain. However, these studies had been discontinued.

Conessine is a plant steroid alkaloid that acts as a potent and specific antagonist of histamine H3 receptors. Conessine displayed high affinity at both rat and human H3 receptors (pKi = 7.61 and 8.27) and generally high selectivity against other sites, including histamine receptors H1, H2, and H4. Conessine was found to efficiently penetrate the CNS and reach very high brain concentrations. Although the very slow CNS clearance and strong binding to adrenergic receptors discouraged focus on conessine itself for further development, its potency and novel steroid-based skeleton motivated further chemical investigation. Modification based on introducing diversity at the 3-nitrogen position generated a new series of H3 antagonists with higher in vitro potency, improved target selectivity, and more favorable drug-like properties. Conessine also has high affinity for the adrenergic receptors. Conessine has being shown to possess anti-malarial activity. In India conessine finds therapeutic use for treatment of dysentery and helminthic disorders.

m-Chlorophenylpiperazine (meta-chlorophenylpiperazine or mCPP) is a psychoactive substance, which is illegal in many countries but can be found on the black market. It induces endocrine, neurological and psychiatric effects. mCPP is a partial agonist at the 5-HT2C receptor but antagonized the 5-HT2B and 5-HT3 receptors. mCPP is also an active metabolite of the drug trazodone, which is used as an effective antidepressant drug with a broad therapeutic spectrum, including anxiolytic efficacy. It is known, that mCPP induces migraine attacks and that the decrease of food intake induced by the mCPP depends on its ability to act as a serotonin agonist is a brain.