PF-4778574 is a potent AMPA receptor positive allosteric modulator (PAM) that has been shown to enhance cognition in animal models.Displacement studies using [3 H]PF-04725379 in rat cortical tissue determined a Ki of 85 nM for PF-4778574. The AMPAR potentiator PF-4778574 was characterized in a series of in vitro assays and acute-dose animal studies evaluating AMPAR-mediated mechanism, safety, and nootropism. Potentiator-induced animal effects were likely purely AMPAR-dependent since PF-4778574 (10 uM) only affected the dopamine transporter (IC50 of 910 nM) in a broad human-based receptor/enzyme selectivity panel.

NS1738 (1-(5-chloro-2-hydroxy-phenyl)-3-(2-chloro- 5-trifluoromethyl-phenyl)-urea) is a positive allosteric modulator of the alpha7 nicotinic acetylcholine receptor (nAChR). NS1738 is capable of producing cognitive enhancement in vivo. NS1738 significantly reduced thermal hyperalgesia in mice.

NS11394 is the novel subtype-selective GABAA receptor-positive modulator which possesses a functional efficacy selectivity profile of alpha5 > alpha3 > alpha2 > alpha1 at GABAA alpha subunit-containing receptors. Compared with other subtype-selective ligands, NS11394 is unique in having superior efficacy at GABAA-alpha3 receptors while maintaining low efficacy at GABAA- alpha1 receptors. NS11394 has an excellent pharmacokinetic profile, which correlates with pharmacodynamics endpoints (CNS receptor occupancy), yielding a high level of confidence in deriving in vivo conclusions anchored to an in vitro selectivity profile and allowing for translation to higher species. Specifically, we show that NS11394 is potent and highly effective in rodent anxiety models. The anxiolytic efficacy of NS11394 is most probably mediated through its high efficacy at GABAA-alpha3 receptors, although a contributory role of GABAA-alpha2 receptors cannot be excluded.

LY404187 (or LY-404,187) is a selective, potent and centrally active positive allosteric modulator of AMPA receptors. LY404187 preferentially acts at recombinant human homomeric GluR2 and GluR4 versus GluR1 and GluR3 AMPA receptors. This drug, developed by Eli Lilly and Company, is a member of biarylpropylsulfonamides. LY404187 has been shown to enhance performance in animal models of cognitive function requiring different mnemonic processes and may be therapeutically beneficial for treating cognitive deficits in a variety of disorders, particularly those that are associated with reduced glutamatergic signaling such as schizophrenia. In addition, LY404187 has been demonstrated to be efficacious in animal models of behavioral despair that possess considerable predictive validity for antidepressant activity and Parkinson's disease.

Isopimaric acid is a widely available tricyclic diterpenoid well represented in the resin of conifers of the genera Pinus, Larix, and Picea. It exhibits interesting biological and pharmaceutical properties such as antimicrobial, antiviral, antiallergenic, and anti‐inflammatory activities. It acts as a large conductance Ca2+activated K+ channel (BK channel) opener. BK channel openers have emerged as potentially useful agents in the therapy of various diseases associated with both the central nervous system and smooth muscle system.

Tetrahydrodeoxycorticosterone (THDOC) is a neuroactive steroid. Neurosteroids represent a class of endogenous steroids that are synthesized in the brain, the adrenals, and the gonads. It potentiates synaptic GABAA-receptor function. THDOC is extremely potent positive allosteric modulators of GABAA receptors with sedative, anxiolytic, and anticonvulsant properties. THDOC can regulate gene expression via the progesterone receptor. The induction of DNA-binding and transcriptional activation of the progesterone receptor requires intracellular oxidation of the neurosteroids into progesterone receptor-active 5 alpha-pregnane steroid. THDOC is involved in the pathophysiology of premenstrual syndrome, catamenial epilepsy, major depression, and stress-sensitive brain disorders.