receptors and potently antagonized R(ϩ)-2-dipropylamino-7-hydroxy-1,2,3,4-tetra-hydronaphtalene HBr (7-OH-DPAT)-induced suppression of cAMP formation (pK b 9.57). In these functional assays, cariprazine showed similar (D 2 ) or higher (D 3 ) antagonist-partial agonist affinity and greater (3-to 10-fold) D 3 versus D 2 selectivity compared with aripiprazole. In in vivo turnover and biosynthesis experiments, cariprazine demonstrated D 2 -related partial agonist and antagonist properties, depending on actual dopaminergic tone. The antagonist-partial agonist properties of cariprazine at D 3 and D 2 receptors, with very high and preferential affinity to D 3 receptors, make it a candidate antipsychotic with a unique pharmacological profile among known antipsychotics. Dopamine D 3 receptors, cloned in the beginning of the 1990s (Sokoloff et al., 1990), are most abundant in the mesolimbic regions (i.e., nucleus accumbens, island of Calleja) where dysregulation of neurotransmission is thought to be associated with psychosis. The discovery that most antipsychotics, in addition to binding to D 2 receptors, display reasonably high affinity for D 3 receptors, led to the assumption that these receptors may also be responsible for antipsychotic efficacy (Sokoloff et al., 1995). Unfortunately, the selective D 3Article, publication date, and citation information can be found at

No abstract

No abstract

The quest for NR2B subtype selective NMDA antagonists started almost twenty years ago. The structure of ifenprodil, the prototype of this group of compounds, inspired many medicinal chemists in several research units. Different approaches led to the identification of the pharmacophore and several distinct classes of compounds containing this pharmacophore. From these studies a few drug candidates emerged and clinical trials proved the viability of the concept. This article attempted to follow the evolution from ifenprodil, a multiple ligand, to selective NR2B antagonists.

Dopamine D 3 receptor partial agonism has been suggested as a potential therapeutic intervention in cocaine addiction. )-piperazin-1-yl]-butyl}-4-bromo-benzamide] was identified as a novel selective dopamine D 3 receptor partial agonist and used for testing this hypothesis in animal models. The compound showed nanomolar affinity to human (K i ϭ 6.7 nM) and rat (K i ϭ 1.6 nM) D 3 receptors with an intrinsic activity of approximately 50%. It possessed several hundredfold selectivity over the D 2 receptor. The molecule bound with moderate (100 -250 nM) affinity to 5-hydroxytryptamine 1A (5-HT 1A ) and nonselectively labeled opiate receptors. RGH-237 proved to be practically inactive on more than 40 other targets, including monoaminergic, cholinergic, GABAergic, and glutamatergic receptors. In rats orally administered RGH-237 was well and rapidly absorbed yielding 41% oral bioavailability. At its pharmacologically active dose (10 mg/kg p.o.), the brain concentration of RGH-237 reached 110 ng/g. Its blood and brain levels were sustained for 3 h. RGH-237 at the oral dose of 10 mg/kg moderately but significantly inhibited the acquisition of cocaine-induced place preference, although by itself, it had no place-conditioning effect. The compound did not affect fixed ratio 1 cocaine self-administration. In a reinstatement paradigm of cocaine self-administration, the compound potently and dose-dependently blocked the cue-induced cocaine-seeking behavior of rats at 10 and 30 mg/kg oral doses. RGH-237 did not affect seeking activity for natural rewards, such as sucrose and water. It did not exert notable effect on spontaneous motor activity of rats. Our results demonstrate that selective D 3 partial agonists may be an effective therapeutic means in the treatment of cocaine abuse.In recent years, a growing body of evidence has accumulated from animal studies demonstrating the importance of dopamine D 3 receptors in mechanisms of cocaine addiction. Nonselective D 2 -like dopaminergic agonists were shown to mimic the effects of cocaine in drug discrimination (Spealman, 1996) as well as in cocaine self-administration paradigms (Caine et al., 1997, Parsons et al., 1996, and the order of potency of the compounds highly correlated with their in vitro affinity and functional activity on D 3 but not on D 2 receptors (Spealman, 1996;Caine et al., 1997). In addition, nafadotride, a modestly selective D 3 receptor antagonist (Sautel et al., 1995), decreased the reinforcing effect of cocaine in the latter method (Caine et al., 1997). Furthermore, the partial D 3 agonist compound BP-897 (Pilla et al., 1999) and the highly selective D 3 full antagonist SB-277011-A (Reavill et al., 2000) were reported to decrease cue-induced drug seeking under a second-order schedule of cocaine selfadministration (Pilla et al., 1999;Di Ciano et al., 2003).More important and clinically more relevant are the findings obtained with dopamine D 3 receptor ligands in various paradigms of reinstatement of cocaine seeking, which model Article, publication ...