Talaglumetad (also known as LY-544344) is a bicyclohexane derivative patented by Eli Lilly and Company as modulators of metabotropic glutamate receptor. Talaglumetad acts as a prodrug of Eglumegad, a selective agonist of metabotropic glutamate receptors (mGluR2/3) and metabolized to release active compound by both human jejunal homogenates and rat liver homogenates. In experiments on mice, Talaglumetad was found to be as effective as diazepam for treating anxiety symptoms in several standard tests, but without producing any of the negative side effects of diazepam such as sedation and memory impairment.

PF-03654746 is a potent, selective antagonist of the human H3 receptor, developed by Pfizer. It was in the clinical trial phase II for the treatment of excessive daytime sleepiness (EDS) associated with narcolepsy, Tourette syndrome as well as potential anti-allergy applications and in phase I of clinical trial for the treatment of Schizophrenia and Alzheimer's disease, but these investigations were discontinued.

Idazoxan is an alpha2 receptor antagonist which also shows activity at imidazoline I1 and I2 receptors and modulates the release of dopamine. Idazoxan was in phase II development in the US. Later the development of idazoxan for schizophrenia was discontinued. It was also in clinical trials for cognition disorders in United Kingdom, and was also discontinued. Idazoxan is used in scientific research as a tool for the study of alpha 2-adrenoceptors.

JNJ-37822681 is a novel, potent, specific, centrally active, dopamine D2 receptor antagonist, which was developed by Johnson & Johnson. This drug is in the phase II of clinical trial for the treatment of schizophrenia. JNJ-37822681 has optimal brain disposition and somnolence was the most frequently reported adverse effect.

ADX-71149 (JNJ-40411813), a phenylpiperidine-substituted pyridone, is positive allosteric modulator (PAM) metabotropic glutamate type 2 (mGlu2) receptor activity. In fed rats, JNJ-40411813 was rapidly absorbed with an absolute oral bioavailability of 31%. ADX-71149 (JNJ-40411813) demonstrates antipsychotic activity in vivo rodents experiments. ADX-71149 (JNJ-40411813) is being jointly developed by Addex Therapeutics and Janssen Pharmaceuticals, a Johnson & Johnson company, for the treatment of epilepsy. Addex Therapeutics was also developing the candidate for schizophrenia, major depressive disorder and anxiety disorders. However, development in these indications has been discontinued.

TAK-063 is a highly potent, selective, and orally active phosphodiesterase 10A (PDE10A) inhibitor with IC50 of 0.30 nM; >15000-fold selectivity over other PDEs. TAK-063 is currently being evaluated in clinical trials for the treatment of schizophrenia. Phosphodiesterase 10A (PDE10A) is a cAMP/cGMP phosphodiesterase highly expressed in medium spiny neurons (MSNs) in the striatum. TAK-063 represents a promising drug for the treatment of schizophrenia with potential for superior safety and tolerability profiles.

Tetrahydropalmatine is a tetrahydroprotoberberine isoquinoline alkaloid that is a primary active constituent of herbal preparations containing plant species of the genera Stephania and Corydalis. The levo isomer of THP (L-THP) appears to contribute to many of the therapeutic effects of these preparations. The pharmacological profile of L-THP, which includes antagonism of dopamine D1 and D2 receptors and actions at dopamine D3, suggests that it may have utility for treating addiction. Clinical trials where L-THP was used for the treatment of cocaine and heroin addiction have promising results. The clinical trial is planned for the treatment of schizophrenia. L-Tetrahydropalmatine is recorded in the Chinese pharmacopoeia.

CYR-101 (MIN-101) is a cyclic amide derivative that has high equipotent affinities for 5-HT2A and sigma-2 receptors (Ki of 7.53 nM and 8.19 nM for 5-HT2A and sigma-2, respectively). MIN-101 also shows binding affinity for a1-adrenergic receptors but low or no affinity for muscarinic, cholinergic, and histaminergic receptors. MIN-101 demonstrated statistically significant efficacy in reducing negative symptoms and good tolerability in stable schizophrenia patients. The drug is in phase II clinical trials for the treatment of Schizophrenia.

Encenicline (EVP-6124; MT-4666) acts as a potent partial and selective agonist at alpha-7 nicotinic acetylcholine receptor. Encenicline significantly improved memory function in animal models. FORUM Pharmaceuticals (formerly EnVivo Pharmaceuticals) is developing encenicline for the treatment of cognition disorders such as schizophrenia and for Alzheimer's disease.

AVL-3288 is a type I selective positive allosteric modulator of α7 nACHRs. It represents a "first-in-class" drug for the treatment of cognitive deficits in CNS disorders such as schizophrenia and potentially other diseases of cognitive impairment such as Alzheimer’s disease and ADHD. AVL-3288 was successfully tested in representative animal models of cognitive dysfunction in schizophrenia, a disease where α7 nAChR function is impaired. To date, no specific treatments for cognitive deficits in schizophrenia exist and approved therapies do not satisfactorily improve cognition. AVL-3288 is currently in human phase I trials.