RESUMEN
Ranitidine (1), the histamine H2-receptor antagonist, has been previously reported to increase gastric emptying and gastric motility by inhibition of acetylcholinesterase (AChE) and enhancement of acetylcholine (ACh) release. In order to obtain potent gastroprokinetic agents, a new series of ranitidine derivatives (5-32) possessing a nitrogen atom instead of a sulfur atom (B) was synthesized and their AChE inhibitory activity and potentiating action on electrically evoked contractions of guinea pig ileum were evaluated. Modification of substituents R1 and R2 markedly influenced the activities. In particular, compound 19, (1-[2-[[[5-(piperidinomethyl)-2-furanyl]methyl]amino]-ethyl]-2- imidazolidinylidene)propanedinitrile fumarate, showed 20 and 100 times more potent AChE inhibitory activity and potentiating action on the ileal contraction, respectively, than ranitidine. Furthermore, compound 19 (KW-5092) enhanced gastrointestinal motility in anesthetized rabbits along with a negligible histamine H2-receptor blocking activity.
Asunto(s)
Inhibidores de la Colinesterasa/síntesis química , Motilidad Gastrointestinal/efectos de los fármacos , Imidazoles/síntesis química , Nitrilos/síntesis química , Ranitidina/análogos & derivados , Animales , Inhibidores de la Colinesterasa/farmacología , Estimulación Eléctrica , Cobayas , Íleon/fisiología , Imidazoles/farmacología , Masculino , Estructura Molecular , Contracción Muscular/efectos de los fármacos , Neostigmina/farmacología , Nitrilos/farmacología , Nitrógeno , Conejos , Ranitidina/farmacología , Relación Estructura-ActividadRESUMEN
Recently, we reported that a ranitidine derivative 2 (fumarate: KW-5092), which had a 2-imidazolidinylidene propanedinitrile moiety (A), showed potent gastrointestinal motility enhancing activity. We have also found that introduction of substituents such as benzyl or 4-fluorobenzyl (i.e., giving 3 or 4) at the N-3 position of the moiety (A) significantly increased this activity. In this study, novel 2-imidazolidinylidene propanedinitrile derivatives possessing a thioether 5-15 were prepared and evaluated for in vitro assays; acetylcholinesterase (AChE) inhibitory activity and potentiating action on electrically induced contractions of guinea pig ileum. Compound 5, in which a nitrogen atom of compound 2 was replaced by a sulfur atom, was more potent than 2 in these tests. Also, in a series of thioether derivatives, introduction of substituents at the N-3 position of the 2-imidazolidinylidene propanedinitrile moiety markedly influenced both activities. In particular, compounds 12 and 13, which showed an excellent potency during in vitro study (AChE IC50 = 3.6 and 2.7 nM; ES. EC30 = 2.1 and 2.5 nM, respectively), were found to be more active in the enhancement of gastrointestinal motility in anesthetized rabbits than their corresponding parent compounds 3 and 4, respectively. In addition, compounds 12 and 13 showed lower affinity for the histamine H2-receptor than ranitidine. Therefore, these compounds may be potent and selective stimulators of gastrointestinal motility.
Asunto(s)
Motilidad Gastrointestinal/efectos de los fármacos , Imidazoles/síntesis química , Nitrilos/síntesis química , Acetilcolinesterasa/metabolismo , Animales , Presión Sanguínea/efectos de los fármacos , Química Encefálica/efectos de los fármacos , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Cobayas , Antagonistas de los Receptores H2 de la Histamina/síntesis química , Antagonistas de los Receptores H2 de la Histamina/química , Antagonistas de los Receptores H2 de la Histamina/farmacología , Íleon/efectos de los fármacos , Imidazoles/química , Imidazoles/metabolismo , Imidazoles/farmacología , Técnicas In Vitro , Masculino , Estructura Molecular , Contracción Muscular/efectos de los fármacos , Nitrilos/química , Nitrilos/metabolismo , Nitrilos/farmacología , Conejos , Ranitidina/análogos & derivados , Ratas , Receptores Histamínicos H2/metabolismo , Sulfuros/análisisRESUMEN
A tetrahydropyran-based inhibitor (2) of mammalian ribonucleotide reductase (mRR) has been designed and synthesized based on the heptapeptide, N-AcFTLDADF (1), corresponding to the C-terminus of the R2 subunit of mRR. Inhibition studies revealed that 2 is indeed a competent inhibitor, albeit less potent than 1.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Piranos/síntesis química , Ribonucleótido Reductasas/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Modelos Moleculares , Piranos/farmacología , Relación Estructura-ActividadRESUMEN
In a previous paper, we reported that a novel ranitidine derivative 2 (fumarate: KW-5092), which had a 2-imidazolidinylidene propanedinitrile moiety (A), showed potent gastrointestinal motility enhancing activity. In order to obtain more potent gastrointestinal motility enhancing agents than compound 2 and to examine the effects of various substituents both at a nitrogen atom (B) in the 2-imidazolidinylidene propanedinitrile moiety and a basic nitrogen atom (C), compounds 5-29 were synthesized and evaluated for acetylcholinesterase (AChE) inhibitory activity and potentiating action on electrically stimulated contractions of guinea pig ileum. Introduction of alkyl, benzyl, aryl or acyl groups to the nitrogen (B) or (C), remarkably influenced both activities. Among these, compounds 14 and 15 showed more potent AChE inhibitory activity (IC50 = 6.7, 6.8 nM, respectively) than compound 2 and were active in potentiating action on the ileal contraction (EC30 = 9.5, 11 nM, respectively) together with a negligible histamine H2-receptor blocking property. Furthermore, these compounds were found to be more effective in the enhancement of gastrointestinal motility in anesthetized rabbits than compound 2.