RESUMEN
para-Methoxymethamphetamine (PMMA), a structural hybrid of two central stimulants, lacks stimulant properties but behaves in a manner similar to that of MDMA [N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane]. PMMA has been established as a training drug in drug discrimination studies, and in the present investigation we sought to determine which optical isomer of PMMA is primarily responsible for its stimulus effects. Because PMMA is a conformationally flexible molecule, it was also of interest to determine what conformation is most important for its actions. Accordingly, we prepared and examined S(+)PMMA, R(-)PMMA, and conformationally restricted forms of PMMA: PMMA-AT, TIQ-1, and TIQ-2. S(+)PMMA (ED50 = 0.32 mg/kg) was found to be at least as potent as PMMA (ED50 = 0.41 mg/kg), whereas R(-)PMMA failed to result in complete stimulus generalization. An aminotetralin-like conformation, as found in PMMA-AT (ED50 = 0.29 mg/kg), seems to better account for the actions of PMMA than a tetrahydroisoquinoline-like conformation because TIQ-1 and TIQ-2 failed to result in stimulus generalization. The results of the present study further support the concept that PMMA and MDMA share considerable similarity with respect to their stimulus properties in animals except that PMMA lacks the amphetaminergic stimulant component of action associated with MDMA.
Asunto(s)
Polimetil Metacrilato/farmacología , Vasodilatadores/farmacología , Animales , Relación Dosis-Respuesta a Droga , Masculino , Conformación Molecular , Conformación Proteica , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of bivalent ligands (2-8) derived from 2,2-diphenyl-[1,3]-dioxolan-4-ylmethyl-dimethylamine methiodide 1 has been synthesized and tested to evaluate affinity and selectivity for M1, M2 and M3 muscarinic receptor subtypes. In order to study the contribution of the spacer and of a second cationic head to the binding process, unsymmetrical ligands (9,10) have also been prepared. The results, expressed in terms of pA2 values, show that, although the spacer negatively affects the interaction of the bivalent ligands with the three receptor subtypes, affinity and selectivity are modulated by its length; this indicates that the pharmacophore binding sites are organized differently with respect to their mutual proximity and orientation, in each receptor subtype.
Asunto(s)
Dioxolanos/síntesis química , Parasimpatolíticos/síntesis química , Receptores Muscarínicos/metabolismo , Cloruro de (4-(m-Clorofenilcarbamoiloxi)-2-butinil)trimetilamonio/antagonistas & inhibidores , Cloruro de (4-(m-Clorofenilcarbamoiloxi)-2-butinil)trimetilamonio/farmacología , Animales , Función Atrial , Carbacol/farmacología , Dioxolanos/farmacocinética , Dioxolanos/farmacología , Estimulación Eléctrica , Cobayas , Atrios Cardíacos/efectos de los fármacos , Íleon/efectos de los fármacos , Técnicas In Vitro , Contracción Isométrica/efectos de los fármacos , Ligandos , Masculino , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Contracción Miocárdica/efectos de los fármacos , Parasimpatolíticos/farmacocinética , Parasimpatolíticos/farmacología , Conejos , Conducto Deferente/efectos de los fármacosRESUMEN
A series of 1,3-dioxolane-based ligands, bearing hydroxymethyl or ester functionalities, was synthesized and tested as potential muscarinic antagonists. The compounds display moderate to low affinity for the three receptor subtypes M1-M3, with some of them showing a significant selectivity for the M3 subtype. The configurational and conformational properties were studied using NOE experiments and vicinal coupling constants. The 1H and 13C NMR chemical shifts show stereochemically dependent trends. Quantitative analysis of conformer populations showed that the exocyclic CH2N CH3)3 group is prevalently in a pseudo-axial orientation in the cis isomers and in a pseudo-equatorial orientation in the trans isomers.
Asunto(s)
Dioxolanos/química , Dioxolanos/farmacología , Antagonistas Muscarínicos/química , Antagonistas Muscarínicos/farmacología , Animales , Dioxolanos/síntesis química , Cobayas , Íleon/efectos de los fármacos , Íleon/metabolismo , Espectroscopía de Resonancia Magnética , Masculino , Modelos Moleculares , Estructura Molecular , Antagonistas Muscarínicos/síntesis química , Miocardio/metabolismo , Conejos , Relación Estructura-Actividad , Conducto Deferente/efectos de los fármacos , Conducto Deferente/metabolismoRESUMEN
A series of 1,3-dioxolane-based ligands, bearing ether, thioether and related sulfoxide and sulfone functionalities, were synthesised and tested as potential muscarinic antagonists. The compounds display moderate to low affinity for the three receptor subtypes M1-M3, with some of them showing a significant selectivity for the M1-M3 over the M2 subtype.
Asunto(s)
Dioxolanos/síntesis química , Antagonistas Muscarínicos/síntesis química , Sulfonas/síntesis química , Sulfóxidos/síntesis química , Animales , Dioxolanos/química , Dioxolanos/farmacología , Cobayas , Corazón/efectos de los fármacos , Íleon/efectos de los fármacos , Técnicas In Vitro , Masculino , Antagonistas Muscarínicos/química , Antagonistas Muscarínicos/farmacología , Conejos , Receptor Muscarínico M1 , Receptor Muscarínico M2 , Receptor Muscarínico M3 , Receptores Muscarínicos/efectos de los fármacos , Relación Estructura-Actividad , Sulfonas/química , Sulfonas/farmacología , Sulfóxidos/química , Sulfóxidos/farmacología , Conducto Deferente/efectos de los fármacosRESUMEN
To characterize the structure-activity relationship between alpha 1-adrenergic receptors and the family of imidazoline/guanidinium receptive sites (IGRS), we synthesized and characterized a series of analogues of cirazoline, an imidazoline with high affinity for alpha 1-adrenergic receptors and IGRS. Analysis of potency, affinity and efficacy of the synthesized molecules indicate different structure-activity relationships for IGRS and alpha-adrenergic receptors. Cirazoline exhibits a 25-fold higher affinity for IGRS (pKi 7.9) than for alpha 1-adrenergic receptors. Replacement of the cyclopropyl ring with an isopropoxy group resulted in a molecule that was 20-fold more selective for alpha 1-adrenergic receptors than for IGRS, i.e. a 500-fold increase in selectivity relative to cirazoline. The unsubstituted derivative 3 and the methyl and allyl substituted analogues 4 and 12 are of particular interest: compounds 3 and 4 recognize IGRS with high affinity (pKi 7.83 and 8.17) and high selectivity (398 and 123) with respect to the alpha 1-adrenergic receptor; compound 12 also recognizes IGRS with high affinity (pKi 8.08) and high selectivity (228 and 138) with respect to the alpha 2B and alpha 2C-adrenergic receptor subtypes. Thanks to their IGRS selectivity, these compounds represent novel and valuable pharmacological tools for the characterization and elucidation of the physiological role of these novel sites.