CP-226269

Interaction at dopamine D4 receptors may improve cognitive function, which is highly impaired in individuals with schizophrenia, but comparative studies of recent antipsychotics in cellular models of D4 receptor activation are lacking. Here, we report the in-vitro profile of over 30 ligands at recombinant hD4.4 receptors. In [35S]GTPgammaS binding experiments using membranes of CHO-hD4.4 cells, apomorphine, preclamol and the selective D4 agonists, ABT724, CP226269, Ro-10-5824 and PD168077, behaved as partial agonists (Emax 20-60% vs. dopamine), whereas L745870 and RBI257, displayed antagonist properties. The 'conventional' antipsychotic, haloperidol and the 'atypicals', clozapine and risperidone, exhibited antagonist properties, while 'third generation' compounds bifeprunox, SLV313 and F15063, acted as partial agonists (10-30%). Aripiprazole and SSR181507 slightly stimulated [35S]GTPgammaS binding at micromolar concentrations. In Xenopus laevis oocytes co-expressing hD4.4 receptors with G-protein-coupled inwardly rectifying potassium (GIRK) channels, apomorphine, preclamol, ABT724, CP226269, and PD168077 stimulated GIRK currents (Emax 70-80%). The 5-HT1A receptor ligands, WAY100635 and flibanserin, also exhibited partial agonist activity (30% and 15%, respectively). Haloperidol, clozapine, olanzapine and nemonapride did not stimulate GIRK currents, whereas aripiprazole, bifeprunox, SLV313 and F15063, but not SSR181507, exhibited partial agonism (Emax 20-35%). In-vitro responses depended on experimental conditions: increasing NaCl concentration (30 mm to 100 mm) reduced agonist efficacy in [35S]GTPgammaS binding, whereas decreasing the amount of hD4.4 cRNA injected into oocytes (from 2.0 to 0.5 ng/oocyte) reduced agonist efficacy of several compounds. These data indicate that, unlike conventional or 'atypical' antipsychotics, several 'third generation' agents display D4 receptor partial agonism that may be sufficient to influence physiological D4 receptor activity in vivo.

The recent development of a highly selective dopamine D4 receptor agonist, A-412997 (2-(3',4',5',6'-tetrahydro-2'H-[2,4'] bipyridinyl-1'-yl)-N-m-tolyl-acetamide), has provided a pharmacological tool with which to conduct systematic investigations into the putative role for dopamine D4 receptors in the central nervous system. These present studies evaluated the potential cognitive enhancing properties of A-412997 in rat models of ADHD (5-trial repeated acquisition inhibitory avoidance in Spontaneous Hypertensive Rat pups) and short-term memory (Social Recognition), in comparison with the less selective dopamine D4 receptor agonists PD168077 and CP226269. A-412997 showed significant dose-dependent efficacy in both models. PD168077 repeatedly improved acquisition in the 5-trial inhibitory avoidance model but failed to reach significance at any dose tested, although significantly improved social recognition was observed (albeit less potent than A-412997). CP226269 showed a significant enhancement in the 5-trial inhibitory avoidance model. These results support a role for the dopamine D4 receptor subtype in cognition.