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Based on N-alkylated 1,2,3,4-tetrahydroisoquinoline derivatives, which are structurally related to the partial agonist BP 897, a series of novel, selective dopamine D3 receptor antagonists has been synthesised. Derivatisation included changes in the arylamide moiety and the tetrahydroisoquinoline substructure leading to compounds with markedly improved selectivities and affinities in the low nanomolar concentration range. From the 55 structures presented here, (E)-3-(4-iodophenyl)-N-(4-(1,2,3,4-tetrahydroisoquinolin-2-yl)butyl)acrylamide (51) has high affinity (Ki(hD3)=12 nM) and a 123-fold preference for the D3 receptor relative to the D2 receptor subtype. Its pharmacological profile offers the prospect of a novel radioligand as a tool for various dopamine D3-receptor-related in vitro and in vivo investigations.

Hedonic and reinforcing properties of drugs of abuse are closely related to brain dopamine neuron activity. All these drugs increase dopamine release in the shell of the nucleus accumbens, a brain region in which neurons co-express the D1 (D1R) and D3 (D3R) dopamine receptor subtypes, that converging pharmacological, human post-mortem and genetic studies suggest to be implicated in drug addiction. The D3R through a cross-talk with the D1R, is involved in induction and expression of behavioral sensitization to levodopa in rats bearing unilateral lesions of dopamine neurons. Behavioral sensitization, a cardinal feature of addiction arises from repeated administration of drugs of abuse thought to play a role in intensification of reinforcing efficacy of these drugs observed under certain conditions. Stimulation of the D3R also appears to enhance the reinforcing effect of cocaine in rats. By interacting with these processes, D3R agents have potential therapeutic applications for treating drug addiction. BP 897 (N-[4-(4-(2-methoxyphenyl)piperazin-1-yl) butyl] naphtalen 2-carboxamide dichlorhydrate), a partial and highly selective D3R agonist in vitro, behaves as an agonist or an antagonist in vivo depending on the response considered. BP 897 has the unprecedented property to reduce cocaine-seeking behavior induced by presentation of a cocaine-associated cue, without having any intrinsic reinforcing effect. As drug-associated cues maintain drug-seeking in animals and elicit craving and relapse in humans, D3R agents like BP 897 may represent new medications for drug addiction, with minimal liability to maintaining dependence.

With a straightforward seven-step synthesis, racemic perhydro[1,4]benzoxazin-6-on was synthesized in overall good yields via regioselective epoxid ring-opening to the corresponding β-aminoalcohol. The oxazine derivative was the key intermediate for the preparation of heteroaromatic analogues of the dopamine D 3 -receptor preferring agonist PD 128,907. The morpholine moiety of PD 128,907 was incorporated in diazole and diazine compounds obtained by different ring closure reactions. The target compounds obtained were structurally related to non-ergot heteroaromatic dopamine agonists which display preferential activity at the D 3 receptor, e.g., quinpirole, quinerolane, or pramipexole. The five membered aminothiazole, aminoselenazole, and pyrazole derivatives showed at least one order of magnitude higher binding at the human D 3 receptor than that at the D 2L receptor. Although the novel compounds displayed K i values only in the micromolar concentration range, the most active ones showed full agonist activity in a functional assay on mitogenesis.

Environmental stimuli that are reliably associated with the effects of many abused drugs, especially stimulants such as cocaine, can produce craving and relapse in abstinent human substance abusers. In animals, such cues can induce and maintain drug-seeking behaviour and also reinstate drug-seeking after extinction. Reducing the motivational effects of drug-related cues might therefore be useful in the treatment of addiction. Converging pharmacological, human post-mortem and genetic studies implicate the dopamine D3 receptor in drug addiction. Here we have designed BP 897, the first D3-receptor-selective agonist, as assessed in vitro with recombinant receptors and in vivo with mice bearing disrupted D3-receptor genes. BP 897 is a partial agonist in vitro and acts in vivo as either an agonist or an antagonist. We show that BP 897 inhibits cocaine-seeking behaviour that depends upon the presentation of drug-associated cues, without having any intrinsic, primary rewarding effects. Our data indicate that compounds like BP 897 could be used for reducing the drug craving and vulnerability to relapse that are elicited by drug-associated environmental stimuli.

A series of eight substituted N-(4-(4-(2-halogenophenyl)piperazin-1-yl)butyl)-3-phenylacryl amide derivatives have been synthesized and screened for binding affinities at dopamine hD(2) and hD(3) receptors. All compounds have shown high to remarkable receptor affinities and some have led to distinct selectivity for D(3) receptors. Highest D(3)-receptor affinity has been observed for 3-(4-aminophenyl)-N-(4-(4-(2-fluorophenyl)piperazin-1-yl)butyl)acryl amide (hD(3) K(i) 0.9 nM; hD(2) K(i) 17.4 nM). Selectivity ratio has been best for 3-(4-chlorophenyl)-N-(4-(4-(2-fluorophenyl)piperazin-1-yl)butyl)acryl amide with a 56-fold preference for hD(3) versus hD(2). A functional activity test has been performed by a mitogenesis test for N-(4-(4-(2-fluorophenyl)piperazin-1-yl)butyl)-3,3-diphenylacryl amide, which, surprisingly, has shown full agonist properties.

The dopamine D(3) receptor is recognized as a potential therapeutic target for the treatment of various neurological and psychiatric disorders. Targetting high affinity and D(3) versus D(2) receptor-preferring ligands, the partial agonist BP 897 was taken as a lead structure. Variations in the spacer and the aryl moiety led to N-alkylated 1-(2-methyoxyphenyl)piperazines with markedly improved affinity and selectivity. Molecular modeling studies supported the structural development. Pharmacophore models for dopamine D(2) and D(3) receptor ligands were developed from their potentially bioactive conformation and were compared in order to get insight into molecular properties of importance for D(2)/D(3) receptor selectivity. For the 72 compounds presented here, an extended and more linear conformation in the aliphatic or aryl spacers turned out to be crucial for dopamine D(3) receptor selectivity. Structural diversity in the aryl moiety (benzamides, heteroarylamides, arylimides) had a major influence on (sub)nanomolar D(3) receptor affinity, which was optimized with more rigid aryl acrylamide derivatives. Compound 38 (ST 280, (E)-4-iodo-N-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)cinnamoylamide) displayed a most promising pharmacological profile (K(i) (hD(3)) = 0.5 nM; K(i) (hD(2L)) = 76.4 nM; selectivity ratio of 153), and above that, compound 38 offered the prospect of a novel radioligand as a pharmacological tool for various D(3) receptor-related in vitro and in vivo investigation.

Dopamine agonist-induced hypothermia has been proposed to be mediated by the D3 receptor (D3R), as it is elicited by (+)7-OH-DPAT and antagonized by S 14297, two putative D3R-preferential ligands. Here we show, however, that S 14297 is a full and partial agonist at D3R and D2R, respectively. Hypothermia was induced in rats by agonists with potencies correlated with their D3R and D2R functional potencies, and was reversed by antagonists, with a rank order of potency typical of the D2R. Moreover, BP 897, a highly potent and selective but partial D3R agonist was inactive in producing hypothermia or reversing (+)7-OH-DPAT-induced hypothermia. (+)7-OH-DPAT was as potent and efficient in inducing hypothermia in wild-type as in D3R-deficient mice. Hence, our results suggest that hypothermia does not result from a selective stimulation of the D3R.

We measured the affinities of bromocriptine, pramipexole, pergolide and ropinirole at human recombinant dopamine D1, D2 and D3 receptors in binding and functional tests. All four compounds bound with high affinity at the dopamine D3 receptor; bromocriptine and pergolide also had high affinity for the dopamine D2 receptor, while only pergolide had significant, although moderate, affinity for the dopamine D1 receptor. Only pergolide had high potency and intrinsic activity at the dopamine D1 receptor for stimulating cyclic AMP accumulation. In addition, the potencies and efficacies of pergolide and bromocriptine, as well as that of dopamine, at the dopamine D1 receptor were increased in the presence of forskolin, an adenylate cyclase activator. All four compounds were highly potent agonists at dopamine D2 and D3 receptors, as measured in a mitogenesis assay. Bromocriptine was ten times more potent and pramipexole and ropinirole ten times less potent at the dopamine D2 than at the dopamine D3 receptor, whereas pergolide was equipotent at the two receptors. These results suggest that the activity of recently developed antiparkinsonian drugs at either the dopamine D1 or the dopamine D3 and not only the dopamine D2 receptors should be taken into account in analyses of their mechanisms of action in therapeutics.

Les proprietes hedoniques et renforcantes des drogues sont reliees a leur interaction avec les systemes dopaminergiques cerebraux. Toutes les drogues entrainent une elevation de dopamine dans l’ecorce du noyau accumbens, une region cerebrale qui coexprime les recepteurs D1 (RD1) et les recepteurs D3 (RD3) de la dopamine. Le recepteur D3 de la dopamine a ete implique dans des phenomenes de sensibilisation compor~tementale et dans la dependance aux drogues par des donnees pharmaco~logiques et d’etudes post-mortem et genetiques. Des agents selectifs de ce recepteur pourraient presenter un interet therapeutique en interagissant avec les proprietes renforcantes des drogues. Un agoniste partiel et specifique du RD3, le BP 897, presente la propriete de reduire le compor~tement de recherche de drogue induit par la presentation de stimuli environnementaux prealablement associes a la prise de cocaine sans posseder de proprietes renforcantes en lui-meme. Comme ces stimuli environnementaux lies au contexte de la prise de drogue maintiennent le comportement de recherche de drogue chez l’animal et declenchent un besoin irrepressible de prise de drogue et des rechutes chez l’homme, des agents comme le BP 897 representent une classe therapeutique nouvelle, denuee du risque de maintenir une pharmacodependance.