RESUMEN
A series of N6,2-disubstituted adenosine analogues have been synthesized and their functional activity measured against A2a and A1 receptors. Examples of compounds with both a lipophilic N6-substituent and amino-functionalized 2-position were highly active at the A2a receptor on the human neutrophil.
Asunto(s)
Adenosina/química , Adenosina/farmacología , Agonistas del Receptor Purinérgico P1 , Adenosina/análogos & derivados , Antiinflamatorios/química , Proteínas de Unión al GTP , Solubilidad , Relación Estructura-ActividadRESUMEN
Incorporation of D-Pro9 into substance P related peptides is known to enhance neurokinin NK-2 receptor agonist potency and selectivity with respect to other neurokinin receptors. We now report that replacement of D-Trp9 by D-Pro9 in the nonselective neurokinin antagonist [Arg5,D-Trp7,9, Nle11]-SP(5-11) gave a partial agonist with NK-2 receptor selectivity. Further incorporation of Pro10 provided the weak but selective NK-2 antagonist Arg-Ala-D-Trp-Phe-D-Pro-Pro-Nle-NH2 (compound 4; NK-2 pKB = 5.9; NK-1 pKB = 4.7; NK-3 pKB less than 4.6). Addition of a suitable lipophilic N-terminal substituent (e.g. Boc, PhCO, cyclohexylcarbonyl) to this compound greatly enhanced NK-2 antagonist activity (compound 10, GR 83074; NK-2 pKB = 8.2), and combined with further optimization of the N-terminal amino acids, provided the extremely potent and selective NK-2 antagonist PhCO-Ala-Ala-D-Trp-Phe-D-Pro-Pro-Nle-NH2 (compound 34, GR 94800; NK-2 pKB = 9.6; NK-1 pKB = 6.4; NK-3 pKB = 6.0). Compounds of this class produced a potent inhibition of NK-2 agonist-induced bronchoconstriction in the anaesthetized guinea-pig.
Asunto(s)
Neuroquinina A/metabolismo , Oligopéptidos/farmacología , Receptores de Neurotransmisores/antagonistas & inhibidores , Secuencia de Aminoácidos , Animales , Cobayas , Masculino , Datos de Secuencia Molecular , Oligopéptidos/síntesis química , Receptores de Neuroquinina-2 , Relación Estructura-ActividadAsunto(s)
Neuroquinina A/análogos & derivados , Neuroquinina A/antagonistas & inhibidores , Neuroquinina B/análogos & derivados , Neuroquinina B/antagonistas & inhibidores , Sustancia P/análogos & derivados , Sustancia P/antagonistas & inhibidores , Secuencia de Aminoácidos , Animales , Cobayas , Técnicas In Vitro , Mucosa Intestinal/metabolismo , Intestinos/efectos de los fármacos , Intestinos/fisiología , Datos de Secuencia Molecular , Estructura Molecular , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso/metabolismo , Músculo Liso/fisiología , Neuroquinina A/síntesis química , Neuroquinina A/farmacología , Neuroquinina B/síntesis química , Neuroquinina B/farmacología , Conformación Proteica , Ratas , Receptores de Neuroquinina-1 , Receptores de Neuroquinina-2 , Receptores de Neuroquinina-3 , Receptores de Neurotransmisores/efectos de los fármacos , Receptores de Neurotransmisores/metabolismo , Relación Estructura-Actividad , Sustancia P/síntesis química , Sustancia P/farmacologíaRESUMEN
With the aim of finding an antidysrhythmic agent suitable for intravenous or oral administration we have examined a range of steroids carrying basic substituents. The primary screen involved control of cardiac dysrhythmias induced by intravenous infusion of aconitine into pentobarbitone-anaesthetised artificially-respired rats. The best activity was found among a series of 11 alpha-alkylamino steroids and structure-activity studies included modification of the alkylamino group and variation of substituents in ring A and at the 17-position. Good oral and intravenous activity was found among 17 beta-methoxycarbonyl-5 alpha-androstanes and methyl 2 beta-ethoxy-3 alpha-hydroxy-11 alpha-(3-methylbutylamino)-5 alpha-androstane-17 beta-carboxylate hydrochloride (CCI 22277) was selected for more detailed pharmacological study.