Catalogo Articoli (Spogli Riviste)

OPAC HELP

Titolo:
AROMATIC AND AMINE SUBSTITUENT EFFECTS ON THE APPARENT LIPOPHILICITIES OF N-[(2-PYRROLIDINYL)METHYL]-SUBSTITUTED BENZAMIDES
Autore:
SCHMIDT DE; VOTAW JR; KESSLER RM; DEPAULIS T;
Indirizzi:
VANDERBILT UNIV,DEPT PSYCHIAT NASHVILLE TN 37235 VANDERBILT UNIV,DEPT PSYCHIAT NASHVILLE TN 37235 VANDERBILT UNIV,DEPT RADIOL NASHVILLE TN 37235 VANDERBILT UNIV,DEPT PHYS NASHVILLE TN 37235 VANDERBILT UNIV,DEPT CHEM NASHVILLE TN 37235
Titolo Testata:
Journal of pharmaceutical sciences
fascicolo: 3, volume: 83, anno: 1994,
pagine: 305 - 315
SICI:
0022-3549(1994)83:3<305:AAASEO>2.0.ZU;2-B
Fonte:
ISI
Lingua:
ENG
Soggetto:
POTENTIAL ANTIPSYCHOTIC AGENTS; PERFORMANCE LIQUID-CHROMATOGRAPHY; DOPAMINE-D2 RECEPTOR RADIOLIGANDS; PROTONATED BASIC COMPOUNDS; ANTIDOPAMINERGIC PROPERTIES; HIGH-AFFINITY; NEUROLEPTIC AGENTS; I-125 EPIDEPRIDE; D-2 RECEPTORS; ANALOGS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
62
Recensione:
Indirizzi per estratti:
Citazione:
D.E. Schmidt et al., "AROMATIC AND AMINE SUBSTITUENT EFFECTS ON THE APPARENT LIPOPHILICITIES OF N-[(2-PYRROLIDINYL)METHYL]-SUBSTITUTED BENZAMIDES", Journal of pharmaceutical sciences, 83(3), 1994, pp. 305-315

Abstract

Lipophilic properties of 92 dopamine D-2 receptor antagonists belonging to the substituted benzamide class of compounds (orthopramides and methoxysalicylamides) were determined by octadecylsilane reversed-phase HPLC. The apparent lipophilicity at pH 7.5 (log k(w)) was obtained from the chromatographic capacity factors in 0.02 M 3-(morpholino)propanesulfonic acid (MOPS) buffer at various concentrations of methanol. The experimental log k(w) values were validated by comparison with the apparent octanol-water partitioning (log P-app) of 15 compounds of lowto medium lipophilicity. The global lipophilicity of the neutral molecule (log k(w)(o)) was obtained by correcting for ionization of the amine and the phenol, using known relationships for the effects on the pK(a) (where K-a is the dissociation constant) of aromatic and aliphatic substituents. Multiple regression analysis showed that log k(w)(o) can be expressed as the sum of pi contributions and a cross correlationterm (Sigma rho sigma) for interactions between the aromatic substituents. Comparison between the methoxysalicylamide (raclopride) series and the orthopramide (sulpiride) series demonstrated that an aromatic 6-hydroxy group increased log k(w) by 0.4 in the 5-halogen series and by 0.8 in the 5-alkyl series, and that a 6-methoxy group decreased log k(w) by 0.5. These paradoxical effects can be explained by the maskingof the polarity of the amide caused by the 6-hydroxy group forming anintramolecularly hydrogen bond with the amide carbonyl group. Introduction of an additional ortho-methoxy substituent had the opposite effect because the resulting steric hindrance prevents the amide moiety from adopting a coplanar conformation with the benzene ring. The presence of a substituent in the aromatic 3-position lowered log k(w) by 0.3 via a combination of steric and electronic influences on the adjacent 2-methoxy group, causing a weakening of the hydrogen bond between the amide and the oxygen atom of the 2-methoxy group. As a result, halogenand alkyl substituents in the 3-position increase the apparent lipophilicity only half that of similar substituents in the 5-position. Substitution with omega-fluoroalkoxyl groups in the aromatic 2- and 3-positions and with omega-fluoroalkyl groups in the 5-position reduced lipophilicities by 0.5 as compared with the corresponding desfluoro derivatives, thereby making them equivalent to an alkyl derivative with one less carbon atom in the chain. In contrast, substitution on the pyrrolidine nitrogen atom with a 2-fluoroethyl or a 3-fluoropropyl group produced compounds with apparent lipophilicities similar to 1.5 and similar to 0.5 higher, respectively, than those of the corresponding N-ethylderivatives. These effects result from a fluorine-induced decrease ofthe basicity of the amine. With these relationships, the apparent lipophilicities at pH 7.4 were predicted for a series of recently developed benzamide radioligands to evaluate their utility as single photon emission computed topography and positron emission topography imaging agents of the dopamine D-2 receptor in the human brain.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 08/12/19 alle ore 11:08:21