RESUMEN
Previous pharmacological studies of methylated oxotremorine derivatives bearing substituents at the 3-, 4-, and 5-positions of the pyrrolidinone ring have been conducted using racemic mixtures, and not with optically active compounds. The synthesis and radioligand binding data of optically active, methylated oxotremorine derivatives at the 3- and 4-positions are described. There are significant pharmacological differences between the 3- and 4-position derivatives. The 4-position enantiomers have weak, approximately equal affinity and antagonist-like profiles, whereas the 3-position enantiomers have significantly different affinities and partial agonist-like profiles.
Asunto(s)
Oxotremorina/análogos & derivados , Animales , Unión Competitiva , Corteza Cerebral/metabolismo , Guanilil Imidodifosfato/farmacología , Masculino , Metilación , N-Metilescopolamina , Oxotremorina/química , Oxotremorina/metabolismo , Pirenzepina/metabolismo , Quinuclidinil Bencilato/metabolismo , Ratas , Ratas Wistar , Receptores Muscarínicos/metabolismo , Derivados de Escopolamina/metabolismo , EstereoisomerismoRESUMEN
A series of optically pure 2-[substituted-3-aminopropynyl]pyrrolidine derivatives, which are restricted-rotation analogues of the muscarinic agent N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide (BM-5, compound 1), have been prepared from d- and l-proline. The compounds when tested in a series of in vitro muscarinic assays [[3H]CD (cortex), [3H]QNB (cortex), [3H]PZ (cortex), [3H]QNB (heart), [3H]QNB + GppNHp (heart)] were found to have weaker muscarinic properties than compound 1. The decrease in affinity was attributed to the increased size of the molecule resulting from the addition of a methylene group to form the pyrrolidine ring. The use of optically active compounds provided a more detailed examination of the complex pharmacological effects of the flexible muscarinic agent 1. The R enantiomers in the acetamide derivatives 12b, 12d, and 12f had a 5-10-fold greater affinity for the muscarinic receptor than the corresponding S enantiomers. A 5-fold difference or less found in the (R)- and (S)-carbamate derivatives 9, 15, and 16 suggested close overlap of the two enantiomers in the receptor binding domain. The affinity differences found in the enantiomeric acetamido derivatives when compared to those of the carbamate analogues may be the result of limited rotation of the acetamido group.