Fig. 1: Dopamine (DA)–like agonist actions of phencyclidine and LY379268. (A) Phencyclidine recognized the high-affinity state of the D₂ receptor, D₂High, as labelled by [³H]domperidone. The presence of 200 μM guanylylimidodiphosphate abolished this high-affinity component, indicating the agonist nature of this phencyclidine-recognized state (reproduced with permission from Seeman P, Guan H-C. Phencyclidine and glutamate agonist LY379268 stimulate DA D₂High receptors: D₂ basis for schizophrenia. Synapse 2008;62:819-28. ©2008 Wiley-Liss, Inc.13). (B) Phencyclidine inhibited the release of prolactin from anterior pituitary cells in culture (reproduced with permission from Seeman P, Lasaga M. Dopamine agonist action of phenyclidine. Synapse 2005;58:275-7. ©2005 Wiley-Liss, Inc.14). (C) Phencyclidine stimulated the incorporation of [³⁵S]GTP-γ-S in human cloned DA D₂Long receptors (in CHO cells) in the absence of NaCl (top line), as well as in the presence of 120 mM NaCl which was about 25% of that compared with the absence of NaCl (30 min incubation) (modified, with permission13). (D) The glutamate agonist LY379268 recognized the high-affinity state of the D₂ receptor, D₂High, as labelled by [³H]domperidone. The presence of 200 μM guanylylimidodiphosphate abolished this high-affinity component, indicating the agonist nature of this drug-recognized state (with permission from Seeman P, Caruso C, Lasaga M. Dopamine partial agonist actions of the glutamate receptor agonists LY354740 and LY379268. Synapse 2008;62:154-8. ©2008 Wiley-Liss, Inc.16). (E) LY379268 directly inhibited the secretion of prolactin from anterior pituitary cells in culture (with permission16). (F) LY379268 stimulated the incorporation of [³⁵S]GTP-γ-S into DA D₂Long receptors, an effect selectively blocked by 10 μM of the D₂ antagonist S-sulpiride (with permission16).

Fig. 3: (Top) Proposed molecular conformations of dopamine (DA; centre), phencyclidine (left), and LY379268 (right), using Dreiding molecular models to fit onto the tetrahedral model of the D₂ receptor.24 The lone pair of electrons is shown as a balloon that hydrogen bonds with the serine and aspartate amino acid residues of the receptor protein. Although phencyclidine does not have the hydrogen-bonding hydroxyl group, it nevertheless recognizes the D₂High state with a dissociation constant of 3–4 nM. The more potent phenyl-meta-OH-phencyclidine would fit perfectly. (Bottom) Inhibition of [³H](+)PHNO binding to DA D₂High receptors ex vivo. The intravenous injection of phencyclidine or LY379268 inhibited binding of the injected [³H](+)PHNO. The absolute amount of specific binding (i.e., striatum–cerebellum) varied between different batches of rats because the average weight of the rats on the left was 250 g, whereas that on the right was 375 g (modified, with permission from Seeman P, Guan H-C. Phencyclidine and glutamate agonist LY379268 stimulate dopamine D2^High receptors: D₂ basis for schizophrenia. Synapse 2008;62:819-28. ©2008 Wiley-Liss, Inc.13).

Fig. 2: The clinical doses of antipsychotic drugs correlate with their potencies (expressed as dissociation constants, Ki values) at the human cloned dopamine (DA) D₂Long receptor. The doses of chlorpromazine and thioridazine appear disproportionately high, because at least 98% of these molecules bind to plasma proteins; when corrected for such plasma protein binding, the free concentrations of all the antipsychotics correlate even more closely to the drug concentrations (in the plasma water) that block DA D₂ receptors. Note that the DA partial agonists, aripiprazole and bifeprunox, also fit the correlation when using human cloned D₂Long receptors and [³H]raclopride. The glutamate receptor agonists LY354740 and LY379268 have DA partial agonist dissociation constants, Ki^High, of 20–40 nM at the functional DA D₂High receptor, data predicting that compounds of this class would have an antipsychotic action at clinical doses of the order of 100 mg/d⁶ (modified, with permission from Seeman P. Dopamine and schizophrenia. Scholarpedia 2007;2:3634. Revision #3726921).