A series of 3,5-disubstituted N-[(1-ethyl-2-pyrrolidinyl) methyl]-6-methoxysalicylamides was synthesized, starting from the 2,6-dimethoxybenzoic acids, by boron tribromide demethylation of the corresponding 3,5-disubstituted 2,6-dimethoxybenzamides and separation of the two positional isomers. The correct structure assignments were based on selective decoupling studies on their 13C NMR spectra. The salicylamide derivatives were tested for antidopamine activity in vivo by their ability to inhibit the apomorphine syndrome in the rat and in vitro by their ability to displace [3H]spiperone from striatal preparations of the rat brain. The activity seems to reside exclusively in the S enantiomer. Several compounds were considerably more potent than haloperidol, particularly those having an ethyl group in the 3-position and a halogen atom in the 5-position of the aromatic ring. The corresponding 5-alkyl-3-halogen-substituted compounds were much less active. A low acute toxicity was found for the most potent compounds. Some of the salicylamides displayed a 10-20-fold separation between the dose which blocks apomorphine-induced hyperactivity and that which blocks apomorphine-induced stereotypy. One compound, S-(-)-3,5-dichloro-N-[(1-ethyl-2-pyrrolidinyl) methyl]-6-methoxysalicylamide (raclopride, FLA 870) (13) had a stereotypy--hyperactivity separation more than twice that of sulpiride while being 100 times more potent in blocking the apomorphine effects. On this basis, 13 was selected for clinical trials against schizophrenia.
The dependence of intact noradrenergic and serotonergic nerve terminals for the decrease in the number of beta-adrenoceptors and 5-HT2 binding sites in the cerebral cortex produced by long-term treatment of rats with antidepressant drugs was examined. Noradrenergic nerve terminals were destroyed with the selective noradrenaline neurotoxin DSP4, and serotonergic nerve terminals were destroyed with p-chloroamphetamine (PCA). It was found that lesioning of the noradrenergic nerve terminals abolished the decrease in beta-adrenoceptors produced by desipramine, mianserin and zimeldine and partially antagonized that of the beta-adrenoceptor agonist clenbuterol. PCA pretreatment did not antagonize the long-term effects on the beta-adrenoceptor produced by these compounds. Lesioning of serotonergic nerve terminals affected the down-regulation of 5-HT2 binding sites produced by long-term treatment with mianserin, desipramine and amiflamine. DSP4 pretreatment partially abolished the down-regulation of 5-HT2 binding sites produced by long-term treatment with desipramine, while the effects of mianserin and amiflamine were unaffected by pretreatment with DSP4.
The effects of repeated oral administration to rats of three antipsychotic compounds (haloperidol 1 mumol/kg, raclopride 5 mumol/kg and remoxipride 10 mumol/kg) on agonist affinity states of the dopamine-D2 receptor were studied using 3H-spiperone binding to rat striatal homogenates in vitro. The competition between 3H-spiperone and dopamine was analyzed using the iterative nonlinear computer program LIGAND. The treatment of rats with haloperidol, raclopride and remoxipride caused an increased number of striatal dopamine-D2 receptors. In parallel to this increase in Bmax (approximately 50%) there was an increased fraction of the number of receptors being in the D2 (high) affinity state. The affinity of dopamine for the D2 (high) state was not affected while a significant decrease in affinity of dopamine for the D2 (low) state was found. The results are discussed in view of the mechanism of action of the three compounds and of neuroleptics in general.
The influence of temperature on the in vitro binding of 3H-raclopride to rat striatal dopamine-D2 receptors was investigated. The KD-values obtained in Scatchard plots were approximately 1.6 nM at temperatures between 15 degrees and 30 degrees. At 37 degrees the KD-value was found to be 3.0 nM, indicating a lower affinity without affecting the number of the receptors (Bmax). The rate of association of 3H-raclopride to the receptors was decreased with decreasing temperatures, and at 6 degrees more than 150 min. incubation was needed to reach the steady state level. From the association constants, the activation energy of the binding reaction was calculated to be 80 kJ/mol. The driving forces of the binding reaction was suggested to be a change in entropy at temperatures up to 30 degrees but a change in enthalpy at 37 degrees.
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