Potential neuroleptic agents. 4. Chemistry, behavioral pharmacology, and inhibition of [3H]spiperone binding of 3,5-disubstituted N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-methoxysalicylamides

Abstract

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.

Stereospecific reversal of stress-induced anhedonia by mianserin and its (+)-enantiomer

“…That antidepressants reverse CMS-induced anhedonia via the potentiation of DA transmission is indicated by experi-527 ments in which DA receptor antagonists were able to reverse the recovery in sucrose intake in animals successfully treated with both tricyclic and atypical antidepressants (Muscat et al 1990Sampson et al 1991). In the present study, raclopride, a specific D 2 antagonist (De Paulis et al 1986), reversed the antidepressant effects of (_+)-mianserin, and (+)-mianserin. The effect of raclopride was short lasting: recovery of sucrose drinking was again evident on the following, raclopride free test.…”

Reversal of stress-induced anhedonia by the atypical antidepressants, fluoxetine and maprotiline

“…We have previously reported that DA antagonists, administered acutely, reversed the therapeutic effects of tricyclic antidepressants within the chronic mild stress paradigm (Muscat et al 1990;Sampson et al 1991). In the present study, raclopride, a specific D2 antagonist (De Paulis et al 1986), selectively reversed the therapeutic effect of fluoxetine and maprotiline: at the low dose used, raclopride had no effect on sucrose consumption in any of the four nonstressed control groups, or in the non-recovered vehicle-or chlordiazepoxide-treated stressed groups, but profoundly decreased sucrose intake in the two antidepressant-treated stressed groups. The effect of raclopride was short lasting: recovery of sucrose drinking was again apparent on the following, raclopride-free test.…”

“…These data argue strongly that an increase in DA receptor responsiveness may be responsible for the therapeutic action of tricyclic antidepressants in this model (Muscat et al 1990;Sampson et al 1991). We have therefore investigated the role of dopaminergic mechanisms in the actions of fluoxetine and maprotiline, using an acute challenge with a highly selective D2 receptor antagonist, raclopride (de Paulis et al 1986),…”

A Review of the Discovery, Pharmacological Characterization, and Behavioral Effects of the Dopamine D2‐Like Receptor Antagonist Eticlopride

“…Importantly, an interesting in vivo finding was that while apomorphine induced both stereotypy and hyperactivity in the rat, both behaviors are thought to be DA mediated [41–43], H AI is thought to occur through activation of mesolimbic dopaminergic pathways, and S AI through stimulation of nigrostriatal dopaminergic pathways [43,44]; and the ability of DA D2‐like receptor antagonists to inhibit these behaviors can often be described in terms of separation of potency. As stated above, eticlopride was nine times more potent than haloperidol at inhibiting H AI ; however, eticlopride and haloperidol were nearly equipotent at inhibiting S AI , and haloperidol was equipotent in both assays [31,33]. This same phenomenon of separation between inhibition potencies was true for the earlier generation benzamides [45,46] as well as for the more potent 3‐alkyl‐substituted salicylamides [21]; each inhibited H AI at lower doses than required to inhibit S AI .…”