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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 ...

Studies investigating the role of the dopamine D3 receptor in the regulation of motor activity of rodents have used several ligands; however, there have been few comparative studies using agonist-antagonist interactions. In the present study, we compared the effects of dopamine D3 antagonists with different levels of selectivity over D2 receptors (nafadotride, U 99194A and SB 277011) on motor activity as well as on agonist-induced hypoactivity, in mice and rats. Horizontal and vertical movements were measured in photocell activity cages. 7-Hydroxy-2-(di-n-propylamino)tetralin (7-OH-DPAT) and PD 128907 were used as dopaminergic agonists. Both dose-dependently inhibited motor activity in mice and vertical activity in rats, while decreasing horizontal activity of rats at doses of 0.01 and 0.1 mg/kg s.c., with no effect (7-OH-DPAT) or stimulation (PD 128907) at the 1 mg/kg dose. In mice habituated to the activity cage, nafadotride (0.1-3 mg/kg i.p.) caused a dose-dependent decrease in motor activity but did not affect the hypomotility evoked by either 7-OH-DPAT (0.1 mg/kg) or PD 128907 (0.1 mg/kg). In habituated rats it had no significant effect on motor activity and was not able to antagonize the hypoactivity caused by PD 128907 (0.1 mg/kg s.c.). U 99194A (5, 10 and 20 mg/kg s.c.) dose-dependently and significantly increased motor activity in mice and inhibited the effects of both agonists. In rats, nafadotride produced considerable motor stimulation and significantly inhibited the PD 128907-induced decrease in horizontal, but not in vertical, activity. SB 277011 (15-45 mg/kg p.o.) significantly increased motor activity in mice and partially blocked the action of 7-OH-DPAT on vertical, but not on horizontal, activity while against PD 128907, its significant inhibitory effect was restricted to a single dose (20 mg/kg). In habituated rats, SB 277011 (13.5, 20 and 30 mg/kg p.o.) exerted no significant effects on motor activity and did not antagonize the hypoactivity caused by PD 128907. Considerable species differences and movement-type differences (horizontal versus vertical) were observed between the effects of the tested dopamine D2/D3 ligands on motor activity in rodents. The antagonists also differed markedly in the robustness of their action. The poorly D3 selective antagonist, nafadotride, had little effect on motor behaviour. The moderately selective U 99194A exerted marked stimulatory effects on motility, and potently inhibited the actions of agonists. SB 277011, a highly selective dopamine D3 receptor antagonist, showed limited ability to influence the motor activity of rodents.

These results may predict a relapse-preventing action for cariprazine in humans in addition to its already established antipsychotic and antimanic efficacy.

5-Hydroxytryptamine 6 (5-HT6) receptors are involved in learning and memory processes and are discussed as promising targets for the treatment of cognitive impairment in central nervous system disorders. A number of 5-HT6 antagonists are currently in the clinical development for schizophrenia and Alzheimer's disease (AD). There is some discrepancy regarding cognitive efficacy in subjects, and only limited data are available on the role of the 5-HT6 receptor in animal models of psychosis. The aim of this study was to investigate the efficacy of the selective 5-HT6 antagonists, Ro-4368554 (1-10 mg/kg, intraperitoneally) and SB-258585 (3-30 mg/kg, intraperitoneally), in animal models for schizophrenia and AD. Both compounds showed cognition-enhancing effects in object recognition, whereas only SB-258585 was able to prevent the scopolamine-induced deficit in the Morris water-maze test. Neither Ro-4368554 nor SB-258585 prevented scopolamine-induced impairment in contextual fear conditioning. Similarly, both compounds were ineffective on MK-801-induced deficits in contextual fear conditioning and spatial working memory. Ro-4368554, but not SB-258585 reversed the apomorphine-induced deficit in prepulse inhibition. Amphetamine-induced hyperlocomotion was not affected by either compound. Taken together, the overall efficacy of Ro-4368554 and SB-258585 in animal models for AD and schizophrenia is rather limited. These data show moderate efficacy in some models for AD but do not support the therapeutic potential of 5-HT6 antagonists for schizophrenia.

Introduction: Cariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist and serotonin 5-HT1A receptor partial agonist, has two major human metabolites, desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR). The metabolite pharmacology was profiled to understand the contribution to cariprazine efficacy.MethodsIn vitro receptor binding and functional assays, electrophysiology, animal models, microdialysis, and kinetic-metabolism approaches were used to characterize the pharmacology of DCAR and DDCAR. ResultsSimilar to cariprazine, both metabolites showed high affinity for human D3, D2L, 5-HT1A, 5-HT2A, and 5-HT2B receptors, albeit with higher selectivity than cariprazine for D3 versus D2 receptors. In [35S]GTPγS binding assays, cariprazine and DDCAR were antagonists in membranes from rat striatum and from cells expressing human D2 and D3 receptors, and were partial agonists in membranes from rat hippocampus. In cAMP signaling assays, cariprazine, DCAR, and DDCAR acted as partial agonists at D2 and D3 receptors; cariprazine and DDCAR were full agonists, whereas DCAR was a partial agonist at 5-HT1A receptors. Cariprazine, DCAR, and DDCAR were pure antagonists at human 5-HT2B receptors. Cariprazine and DDCAR increased rat striatal dopamine and reduced cortical serotonin turnover. Cariprazine and DDCAR showed similar in vivo D3 receptor occupancy in rat brain; however, cariprazine was more potent for D2 receptor occupancy. Both cariprazine and DDCAR dose-dependently but partially suppressed the spontaneous activity of midbrain dopaminergic neurons in rats, with the parent compound being more potent but shorter acting than its metabolite. Consistent with the D2 receptor occupancy profile, DDCAR was 3- to 10-fold less potent than cariprazine in rodent models of antipsychotic-like activity. Following acute cariprazine administration, DDCAR was detected in the rodent brain but at much lower levels than cariprazine.ConclusionOverall, in vitro and in vivo pharmacological profiles of DCAR and DDCAR demonstrated high similarity with cariprazine, suggesting that the major metabolites of cariprazine contribute significantly to its clinical efficacy.

RG-15 (trans-N-[4-[2-[4-(3-cyano-5-trifluoromethyl -phenyl) -piperazine -1 -yl] -ethyl] -cyclohexyl] -3 -pyridinesulfonic amide dihydro-chloride), is a highly selective dopamine D3/D2 receptor antagonist with subnanomolar affinity for the D3 receptor and nanomolar affinity for the D2 receptor. We found that RG-15 showed a good oral bioavailability (54%) and high brain levels (approx. 900 ng/g) in rats and demonstrated antipsychotic efficacy in amphetamine-induced hyperactivity and conditioned avoidance response tests in rats, yielding ED50 (median effective dose) values of 8.6 and 12 mg/kg orally, respectively. At six- to eightfold higher doses, RG-15 blocked spontaneous motor activity, while a 30 mg/kg dose of the compound caused an increase in the home-cage motility of rats. The drug did not produce catalepsy up to 160 mg/kg oral dose; moreover, it inhibited haloperidol-induced catalepsy in the range 15-60 mg/kg. RG-15 (10 mg/kg orally) restored the impaired learning performance of scopolamine- or diazepam-treated rats in a water-labyrinth paradigm. It is assumed that the motor activating, anticataleptic and cognitive-enhancing properties of RG-15 result from its potent D3 antagonism. In this regard, RG 15 clearly differs from other antipsychotics. Olanzapine, clozapine and amisulpride all showed efficacy against amphetamine-induced hyperactivity and on conditioned avoidance, but compared to RG-15, they proved to be more cataleptogenic and depressed or did not change the home-cage activity of animals. Olanzapine was also inactive in the learning paradigm. Our results suggest that subnanomolar dopamine D3 receptor antagonism coupled to moderate D2 affinity may result in an antipsychotic profile characterised by a lack of extrapyramidal side effects and secondary negative symptoms with simultaneous efficacy on positive and cognitive symptoms of schizophrenia.