Fabrice Garrido

Selective inhibition of cocaine-seeking behaviour by a partial dopamine D3 receptor agonist.

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.

Unprecedented rearrangement reaction of 2-aziridinemethanols with lower order lithium methylcyanocuprate

Abstract Complementary selectivity can be achieved in ring opening reactions of 2-aziridinemethanols by using either the Gilman reagent or lower order cyanocuprate. In the former case, the usual attack of the Gilman reagent to the substrates 1 and 2 results in the formation of the expected ring opening products ( 3 and 4 ) and ( 7 and 8 ), respectively. In contrast, exposure of both 1 and 2 to the lower order cyanocuprate proceeds in an unprecedented fashion, presumably via epoxides D and G , to yield unexpected secondary alcohols ( 11 and 12 ) as the major products.

The dopamine D3 receptor and schizophrenia: pharmacological, anatomical and genetic approaches

Antipsychotic drug therapy mainly rests on the use of antagonists of dopamine D2-like (D2, D3 and D4) receptors, for which all clinically active compounds have high affinity. The D3 receptor has a restricted expression in brain limbic areas, associated with cognitive functions and motivated behavior. D3 selective agonists and antagonists reveal an inhibitory role on motor behaviors for the D3 receptor, opposite to that of the D2 receptor. An opposing role for D2 and D3 receptors is also suggested by the contrasted effects of D2/D3 antagonists on neurotensin expression in discrete subdivisions of nucleus accumbens, where D2 and D3 receptors are selectively expressed. Tolerance to the motor but not to the therapeutic effects of neuroleptics is observed after repeated administration, which upregulates the D2, but not the D3 receptor in animals. In genetic association studies, an excess of homozygosity for both alleles of the BalI polymorphism at the D3 receptor gene was found in schizophrenic patients, suggesting that this gene may have subtle influence on the liability to develop schizophrenia. These results suggest the D3 receptor as an important target for antipsychotic drug action, and D3 receptor selective antagonists as promising therapeutic agents.

SN2′ selective alkylation of allylic chlorides and mesylates with RZnX reagents generated from Grignard reagents, zinc chloride, lithium chloride, and Cu(II)-salts

Abstract Treatment of RMgX (1 equiv. R = alkyl; X = Cl, Br) with ZnCl 2 (1 equiv.) in a mixed solvent of THF and Et 2 O leads to a highly turbid white suspension. Addition of LiCl (1∼2 equiv.) solubilizes the insoluble species to yield a colorless clear solution. Addition of a catalytic amount of a Cu(II)-salt followed by allylic halides or mesylates at 0 °C ∼ room temperature yielded S N 2′products in high yields. Application for the synthesis of ( E )-alkene dipeptide isosteres is also reported.

Practical synthesis of acetophenones from phenoltriflates

Abstract A new practical method for the preparation of acetophenone from aryl triflates is reported. The acyl group is installed by a mixture of SnMe 4 , Pd(0) and CO (balloon), using a three-component procedure.

FRAGMENTATION OF N-BOC ARYLPIPERAZINES UNDER BASIC CONDITIONS

N-Boc arylpiperazines 1a-c under basic conditions (sec-Buli, TMEDA, THF) undergo ring opening fragmentation to yield arylethylenediamines 2a-c, 4a-c at low temperature and arylimidazolidinones 5a-c at higher temperature.