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

• Published in: Journal of medicinal chemistry Vol. 29; no. 1; pp. 61 - 69
• Main Authors: De Paulis, Tomas, Kumar, Yatendra, Johansson, Lars, Raemsby, Sten, Hall, Haakan, Saellemark, Maria, Aengeby-Moeller, Kristina, Oegren, Sven Ove
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01-01-1986
• Subjects: Animals; Apomorphine - antagonists & inhibitors; Chemical Phenomena; Chemistry; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Haloperidol - pharmacology; Male; Raclopride; Rats; Rats, Inbred Strains; Receptors, Dopamine - drug effects; Receptors, Dopamine - physiology; Salicylamides - chemical synthesis; Salicylamides - pharmacology; Salicylamides - toxicity; Spiperone - antagonists & inhibitors; Stereotyped Behavior - drug effects; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00151a010

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.