New SDAs Development loperidone ——— sitrecoaas ee Yost <— — NaA0S62 nomonapride FIGURE 10-38 Serotonin-dopamine antagonists in development. New serotonin-dopamine antagonists currently in development include iloperidone, asenapine, SM13493/lurasidone, blonanserin, nemonapride, NRA0562,and Y931What Makes an Antipsychotic Atypical? FIGURE 10-39 Rapid dissociation of D2 antagonism. In addition to serotonin 24 antagonism, the "atypicality" of an antipsychotic may be related to how quickly it dissociates from the D2 receptor, such that long-lasting binding is a feature of conventional antipsychotics and rapid dissociation is a feature of atypical antipsychotics.Hypothetical Action of a Conventional ‘Antipsychotic Over Time t : “= S FIGURE 10-41 Hypothetical acton of a conventional antipsychotic over time. This figure shows a curve of D2 recepte blockade after two doses ofa conventional atipsychotc as well asthe concomitant clinical effects. Por to dosing a schizophrenic patient wth a conventional antipsychotic (far lef), there is no 02 receptor blockade, ‘and the schizophrenic patent has postive symptoms of psychosis such as delusions and hallucinations. Also, ‘Snoe there is no drug present, there will be no EPS. Folowing a dose ofa conventional antipsychotic (middle), 12 recoptors ae blocked so tightly that they both cause antipsychotic actions and induce EPS. Following another dove ofa conventonal antipsychotic (fr rght), the D2 receptors stay persistent blocked, so that antpsyehote actos are aays assocatd with EPS and eventual tardive dyskinesia may even occuReceptor Binding Properties of | Conventional Antipsychotics | tt, fog esting ning by conventional ai FIGURE 10-40A and B 02 binding of conventional antipsychotics. (A) Shown here is an icon for conventional antipsychotic drugs. Because of the biochemical properties of these drugs, their binding to postsynaptic D2 receptors is tight and long-lasting, as shown by the teeth on the binding site of the conventional antipsychotic. The D2 receptor has grooves at which the teeth of the drug can bind tightly. (B) Here, the conventional antipsychotic is binding to the postsynaptic D2 receptor, with its teeth locking the drug into the receptor binding site to block it in a long-lasting manner. <Receptor Binding Properties of ‘Atypical Antipsychotics FIGURE 10-42A, B and Hitand-un receptor binding properties of atypical antipsychotic. (A) Shown here isthe leon for atypical antipsychotic drugs, Because of their bochamcal nature, the binding of atypical antipsychotics to postsynaptic 02 receptors (shown on the right) is loose, as shown by a smooth binding ste for the atypical antipsychotic that does not fi into the teeth of the recepor. (B) Fist stage of hit-and.cun binding: the hit. Here the atypical anipsychotc is binding tothe D2 receptor. Note that i fs loosely into the D2 recepter without ‘geting locked into the grooves ofthe receptor as do the Conventional antipsychotics. (C) Second stage of hit-and-run binding: the «un, Since an atypical anipsychote fis loosely into the D2 receptors, it sips of easly after binding only beety and then runs avay. This is also called rapid cissoctaton.Hypothetical Action of an Atypical Antipsychotic with Rapid Dissociation Over Time § af PURE 10.4 patel on of ype ayeote ote. Th wee ost sr co tan spe eet a la + : + * Garg eer pein anata ene Pe ‘evan ptr ha poten fen et 8 Fe 104 nena bere mg ripe aire tt 69 cs Pen nag ae Pe cas, co ener apse esWhat Makes an Antipsychotic Atypical? D2 Partial Agonist Actions (DPA) FIGURE 10-45 D2 partial agonism. What makes an antipsychotic atypical? D2 partial agonist actions (DPA). A third property that may render an antipsychotic atypical is that of partial dopamine 2 antagonism. These agents may stabilize dopamine neurotansmission in a state between silent antagonism and full stimulation.\ FIGURE 10-47 Dopamine receptor output, Dopamine sete a fll agonist and causes full receptor output (op) Conventional antipsychotics ar fll antagonists and allow lite Hany receptor output (middle). The same is true for atypical antipsychotic that are serotonin dopamine antagonists. However, D2 pantal agonists can partially activate dopamine receptor output and cause a stablizing balance between stimulation and blockade of dopamine receptors (bottom)Se neMesolimble Pathway High emptor Dopamine Output - Untreated Schizophrenia Mesocortical Mesocortical Nigrostriatal Tuberoinfundibular Pathway Pathway Pathway Pathway to DLPFC to VMPFC = 7 3 Low Low NORHAL ogre aloaive npr symptomsDopamine Output: DPA Oo Mosolimbie Mesocortical Mesocortical Nigrostria Pathway Pathway Pathway Pathway to DLPFC to VMPFC. Tuberoinfuncibular athway NORMAL NORMAL NORMAL NORIAL ‘NORMAL mene ten ho elevatedWhich Antipsychotics Are DPAs? amigulide? \ > pier lonedose suite? FIGURE 10-52 Dopamine partial agonists on the market. Which antipsychotics are DPAs? Dopamine partial ‘agonists that are currently avaiable or soon to be avaliable include aripiprazole, bifeprunex, possibly amisulpride, and perhaps sulpiride when used at low doses.Development cie8 he — Acr.t0e > Pru seamosu sree a \ ssm.181807 ‘noo FIGURE 10-53 Dopamine partial agonists in development. New dopamine partial agonists in development include RGH188, 3PPR bifeprunox, SLV313, SLV314, ACR16, PNU 2639/0SU 6162, CI1007, ACP-104, SSR181507, and sarizotanWhat Makes an Antipsychotic Atypical? ‘Adding SHT1A Agonist/Partial Agonist Actions FIGURE 10-55 SHT1A fullipartial agonism. A fourth property that may contribute to the atypicality of an antipsychotic i full or partial agonism of serotonin 1A receptors. Agonism of serotonin 1A receptors can increase dopamine release, which could improve affectve, cognitive, and negative symptoms while also reducing the risk of extrapyramidal symptoms (EPS) and prolactin elevation. Serotonin 1A agonism can also decrease glutamate release, which could indirectly reduce positive symptoms of psychosisWhich Antipsychotics are SPAs? (Serotonin 1A Partial Agonists)Antipsychotic Binding Propet Hypothetical Media "Thoropeutie ActionsWhich Receptors Hypothetically Mediate Cardiometabolic Risk? FIGURE 10-58 Receptors mediating cardiometabalic risk. Which recaptors hypothetically mediate cardiometabole risk? Serotonn-2C, musearinic-3, and histamine-1 recaps at well as cecaptors yet to be identified (signed hore a8 receptor X), reall hypothatically Inked to cardiometabolc risk. In particular antagonism of serotonin-2C and histamine-1 receptors is associated with weight gain, while antagonism at muscarinic recente can impair insulin regulation, An unknown receptor X may be involve in the rapid Production of insulin resistance and may alsa rapidly cause elevated fasting plasma triglyceride levels in some patients who experence increased cardiometabolc risk on catain alypical antipsychoticsHistamine H1 Combined with Serotonin 2C Antagonism May Stimulate Appetite enhanced copctie FIGURE 10-59 HI combined with SHT2C antagonism. Histamine 1 (HI) combined with seretonin-2C antagonism may stimulate appetite. Antagonism of serotonin-2C andlor HI receptors can lead to weight gain, perhaps a leat in part due fo stimulation of appetite regulated by the hypothalamus.M3 Antagonism and Antipsychotics: actor in DKAMHS?