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.

JNJ-40411813 (aka ADX71149) is a metabotropic glutamate receptor 2 (mGluR2) positive allosteric modulator (PAM) that has the potential to be the first oral non-dopaminergic drug that may address both the positive and negative symptoms of schizophrenia and other indications, such as anxiety. ADX71149 is differentiated from marketed antipsychotics in that it may also show efficacy on negative symptoms and avoid compliance-limiting side effects such as weight gain, hyperprolactinemia and extrapyramidal symptoms, which are associated with the use of dopamine antagonists. The development of ADX71149 is part of a worldwide research collaboration and license agreement between Addex and Janssen Pharmaceuticals, Inc. This drug was also investigated for use as an adjunctive treatment for major depressive disorder (MDD), however, these studies were discontinued. JNJ-40411813 is now in phase II clinical trial for the treatment of epilepsy.

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.

Bitopertin is a Glycine transporter type 1 inhibitor which was developed by Hoffmann-La Roche for the treatment of patients with schizophrenia. The drug was shown to be potent in vitro, however it failed to meet primary endpoints in phase III. Bitopertin was also tested for the treatment of obsessive-compulsive disorder, but the development stopped in phase II.

Synthetic compound Erteberel (LY500307) is a highly potent and selective ERβ agonist; it has a 12-fold higher affinity for ERβ than ERα and exhibits 32-fold more functional potency. LY500307 was well tolerated in benign prostatic hypertrophy (BPH) patients with no side effects and it is currently being tested in phase 2 clinical trials for improving negative symptoms and cognitive impairment associated with Schizophrenia. In BPH clinical trial incidence of adverse events was comparable between treatment groups, and no clinically meaningful changes in laboratory tests were observed.

LY404039 [(-)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]-hexane-4,6-dicarboxylic acid] is an agonist of orthosteric metabotropic glutamate receptor (mGluR)2/3. In addition, it acts as an agonist at dopamine D2 receptors. LY404039 demonstrated broad antipsychotic and anxiolytic efficacy across multiple animal models. LY-2140023 is a methionine amide prodrug of LY-404039 being developed by Eli Lilly & Co for the potential oral treatment of schizophrenia.