ABSTRACT
The possibility that polymethylene tetraamines act as divalent ligands has been explored. Structure-activity relationship studies among polymethylene tetraamines have shown that four nitrogens are necessary for high affinity binding to M2 receptors while being less important for M3 muscarinic receptors. Replacement of one terminal methoxybenzyl group of the potent and selective muscarinic antagonist methoctramine by different moieties led to weaker antagonists suggesting that the two terminal nitrogens of methoctramine interact with two similar receptor sites. Data are presented which suggest that methoctramine might interact with four acidic residues of the receptor: two residues are buried in the third transmembrane segment whereas the others are located extracellularly on the loop 4-5 which may represent the allosteric site where several antagonists such as gallamine bind. An hypothetical model describing the interaction of methoctramine with the M2 receptor is proposed. It may provide a useful working hypothesis for the design of new selective muscarinic ligands.
Subject(s)
Polyamines , Polymers , Receptors, Muscarinic/drug effects , Animals , Humans , Ligands , Polyamines/chemical synthesis , Polymers/chemical synthesisABSTRACT
Several analogues of 2-[[[2-(2,6-dimethoxyphenoxy)ethyl]amino]methyl]-1,4-benzodioxa n (WB 4101, 1) were prepared and evaluated for their blocking activity on alpha 1- and alpha 2-adrenoreceptors in the isolated rat vas deferens. The results were compared with those obtained for 1 and benoxathian (2). It was shown that the two oxygens at positions 1 and 4 may have a different role in receptor binding. It seems that the oxygen at position 4 as such does not contribute to the binding while it is important in stabilizing an optimal conformation for drug-receptor interaction mechanism. On the other hand, the oxygen at position 1 might interact with a receptor polar pocket of reduced size by way of a donor-acceptor dipolar interaction. Furthermore, it was shown that replacement of the dehydrodioxane ring of 1 by a phenyl or a pyrrole nucleus causes a significant decrease in activity.
Subject(s)
Adrenergic alpha-Antagonists/chemical synthesis , Dioxanes/chemical synthesis , Dioxins/chemical synthesis , Adrenergic alpha-Antagonists/pharmacology , Animals , Binding Sites , Chemical Phenomena , Chemistry , Clonidine/pharmacology , Dioxanes/pharmacology , Male , Muscle Contraction/drug effects , Norepinephrine/pharmacology , Oxathiins/pharmacology , Oxygen , Rats , Structure-Activity Relationship , Sulfur , Vas Deferens/drug effectsABSTRACT
Several prazosin-related compounds have been synthesized and evaluated for their blocking activity toward alpha-adrenoreceptors. The structural modification performed on the prazosin structure included the replacement of the piperazine ring with 2,3-dialkylpiperazine or 1,2-cyclohexanediamine moieties to characterize a lipophilic binding pocket in the alpha 1-adrenoreceptor surface. Cyclohexanediamine derivatives 3-6 were almost devoid of potency and selectivity, whereas dialkylpiperazine compounds 7-14 showed high affinity and selectivity toward alpha 1-adrenoreceptors. The cis derivative 13 (cyclazosin) was the most potent and selective with an alpha 1/alpha 2 selectivity ratio value of 7800. The particular trend of antagonist activity within cis/trans stereoisomeric compounds not only supports the presence of a lipophilic binding area on alpha 1-adrenoreceptor surface but also suggests that the lipophilic pocket is endowed with a well-defined size and spatial orientation. The most active compound of the series, 13, was tested also in vivo for antihypertensive activity on spontaneously hypertensive rats. It showed an interesting long-lasting hypotensive effect, very similar to that of doxazosin, which was statistically significant 12 h after oral administration.
Subject(s)
Adrenergic alpha-Antagonists/chemical synthesis , Piperazines/chemical synthesis , Prazosin/analogs & derivatives , Quinazolines/chemical synthesis , Quinoxalines/chemical synthesis , Adrenergic alpha-Antagonists/chemistry , Adrenergic alpha-Antagonists/pharmacology , Animals , Hemodynamics/drug effects , Male , Piperazines/chemistry , Piperazines/pharmacology , Prazosin/pharmacology , Quinazolines/pharmacology , Quinoxalines/pharmacology , Rats , Rats, Inbred SHR , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The effects of N,N-dimethyl-2-bromo-2-phenethylamine hydrobromide (DMPEA) on alpha 1- and alpha 2-adrenoceptors were examined in the isolated rat vas deferens. The active species of DMPEA was the corresponding ethyleniminium ion, which forms in the biophase, since pretreatment of tissues with sodium thiosulphate completely prevented the DMPEA-induced inhibition at alpha 1- and alpha 2-adrenoceptors. DMPEA was approximately 42-fold more potent in inhibiting alpha 2-adrenoceptors than it was in inhibiting alpha 1-adrenoceptors. The antagonism of both receptor types was reversible since washing of the tissues after incubation with DMPEA brought the agonist dose-response curve back to the control value. At alpha 1-adrenoceptors, DMPEA displaced the noradrenaline dose-response curve to the right and concomitantly depressed the maximum response, effects which are consistent with a non-competitive mechanism of action. At alpha 2-adrenoceptors, DMPEA caused a parallel shift of the clonidine or noradrenaline dose-response curve to the right in field-stimulated prostatic portions of the rat vas deferens. The antagonism appeared to be competitive at low concentrations, whereas the shift of the clonidine dose-response curve at higher concentrations became overproportional to the DMPEA concentration. A combination of DMPEA with idazoxan produced a less-than-additive shift of the dose-response curve for clonidine, indicating that these antagonists do not bind to the same site.
Subject(s)
Phenethylamines/metabolism , Receptors, Adrenergic, alpha/metabolism , Vas Deferens/metabolism , Adrenergic alpha-Antagonists/metabolism , Adrenergic alpha-Antagonists/pharmacology , Animals , Clonidine/pharmacology , Dioxanes/pharmacology , Idazoxan , In Vitro Techniques , Male , Muscle Contraction/drug effects , Norepinephrine/pharmacology , Phenethylamines/pharmacology , Rats , Receptors, Adrenergic, alpha/drug effects , Thiosulfates/pharmacology , Vas Deferens/drug effects , Vas Deferens/physiologyABSTRACT
The antimuscarinic effects of tripitramine (1, 1, 24--tris[[5, 11-dihydro-6-oxo-6H-pyrido [2,3-b][1,4]- benzodiazepin-11-yl)carbonyl]methyl]-8, 17-dimethyl-1, 8, 17, 24-tetraazatetracosane tetraoxalate), a member of a series of polymethylene tetraamines with in vitro cardioselectivity, were assessed in two in vivo preparations: anaesthetized and pithed rats. The well-known M2 selective antagonist methoctramine was used in a comparative study. Tripitramine (0.0202 mumol/kg i.v.) proved to be a potent antagonist at cardiac M2 receptors that mediate the decrease in heart rate in the pithed rat; the same dose of this antagonist in the anaesthetized rat did not significantly affect the depressor action of methacholine mediated by vascular M3 receptors. In the pithed rat, this dose did not affect the ganglionic M1 receptor-mediated tachycardia and pressor response to muscarine or McN-A-343. These in vivo data are consistent with the in vitro findings and confirm that tripitramine is a more potent and selective muscarinic M2 receptor antagonist than methoctramine.
Subject(s)
Benzodiazepines/pharmacology , Diamines/pharmacology , Muscarinic Antagonists/pharmacology , Parasympatholytics/pharmacology , Receptors, Muscarinic/drug effects , (4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride/administration & dosage , (4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride/pharmacology , Animals , Benzodiazepines/administration & dosage , Blood Pressure/drug effects , Decerebrate State , Diamines/administration & dosage , Heart Rate/drug effects , Injections, Intravenous , Male , Muscarinic Antagonists/administration & dosage , Rats , Receptors, Muscarinic/metabolismABSTRACT
Synthesis and study of the antimonoamine oxidase activity of some N'-substituted hydrazides of 2-methyl-3-indolizinecarboxylic acid are reported. The activities were generally of about the same order as those of the corresponding hydrazides of 2-indolizinecarboxylic acid.
Subject(s)
Hydrazines/chemical synthesis , Indolizines/chemical synthesis , Animals , Hydrazines/pharmacology , In Vitro Techniques , Indolizines/pharmacology , SwineABSTRACT
In a continuing search for new biologically active agents derived from indolizine, 3-(2-aminoethyl)-2-methylindolizine, 3-(2-aminoethyl)-2-methyl-5,6,7,8-tetrahydroindolizine, and some mono- and di-N-substituted derivatives were prepared. Initial pharmacological screening showed that these compounds possess anti-5-hydroxytryptamine, antihistamine, antiacetylcholine, and CNS-depressant activities.
Subject(s)
Indolizines/chemical synthesis , Acetylcholine/antagonists & inhibitors , Animals , Central Nervous System Depressants/chemical synthesis , Female , Guinea Pigs , Histamine Antagonists/chemical synthesis , In Vitro Techniques , Indolizines/pharmacology , Lethal Dose 50 , Male , Mice , Rats , Serotonin Antagonists/chemical synthesisABSTRACT
The synthesis and antimonoamine oxidase activity of some N'-substituted hydrazides of indolizine-2-carboxylic acid are described. They all inhibit monoamine oxidase and are more active than iproniazid. The structure-activity relationships also are discussed.
Subject(s)
Indolizines/chemical synthesis , Monoamine Oxidase Inhibitors/chemical synthesis , Carboxylic Acids/chemical synthesis , Carboxylic Acids/pharmacology , In Vitro Techniques , Indolizines/pharmacology , Iproniazid/pharmacology , Structure-Activity RelationshipABSTRACT
The syntheses and a preliminary pharmacological evaluation of some aminopropylindolizines and aminopropyltetrahydroindolizines are reported. All compounds showed anti-5-hydroxytryptamine, anti-histamine, and antiacetylcholine activities. Some also exhibited weak CNS activity.
Subject(s)
Indolizines/chemical synthesis , Acetylcholine/antagonists & inhibitors , Animals , Behavior, Animal/drug effects , Female , Guinea Pigs , Histamine H1 Antagonists/chemical synthesis , In Vitro Techniques , Indolizines/pharmacology , Male , Mice , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Propylamines/chemical synthesis , Propylamines/pharmacology , Rats , Serotonin Antagonists/chemical synthesis , Uterine Contraction/drug effectsABSTRACT
Several WB4101 (1)-related compounds were synthesized. Their alpha-adrenoreceptor blocking properties were evaluated in order to understand the kind of interaction occurring between the amine function of (1)-related compounds and the alpha-adrenoreceptor anionic site. The results suggest that a charge reinforced hydrogen bond rather than an ion pairing might play a most important role in receptor binding.
Subject(s)
Adrenergic alpha-Antagonists/chemical synthesis , Dioxanes/chemical synthesis , Adrenergic alpha-Antagonists/pharmacology , Animals , Clonidine/antagonists & inhibitors , Clonidine/pharmacology , Cocaine/pharmacology , Dioxanes/pharmacology , Electric Stimulation , In Vitro Techniques , Male , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Norepinephrine/antagonists & inhibitors , Propranolol/pharmacology , Rats , Structure-Activity Relationship , Vas Deferens/drug effectsABSTRACT
A series of quinazoline derivatives, 2-20, structurally related to the racemic alpha(1)-adrenoceptor antagonist cyclazosin (1), were synthesized and evaluated for their functional antagonism at alpha(1)- and alpha(2)-adrenoceptors and for their binding affinity at human cloned alpha(1a)-, alpha(1b)- and alpha(1d)-adrenoceptor subtypes. They displayed, like 1, preferential antagonism and selectivity for alpha(1) versus alpha(2)-adrenoceptors. Compounds 10, 13, and 18 showed high potency at alpha(1)-adrenoceptors similar to that of 1 (pK(B) values 8.47-8.89 versus 8.67), whereas 13 and 15 were endowed with the highest alpha(1)-adrenoceptor selectivity, only 3- to 4-fold lower than that of 1. In binding experiments, all of the compounds displayed an affinity practically similar to that found for 1, with the exception of 19 and 20 that were definitely less potent. The s-triazine analogue 18 was the most potent of the series with pK(i) values of 10.15 (alpha(1a)), 10.22 (alpha(1b)) and 10.40 (alpha(1d)), resulting 77-fold more potent than 1 at alpha(1a)-adrenoceptors. In addition, the majority of compounds, like prototype 1, showed the same trend of preferential affinity for alpha(1d)- and alpha(1b)-adrenoceptors that alpha(1a)-subtype. In conclusion, we identified compounds 2-5, 10, 12 and 13, bearing either an aliphatic- or an arylalkyl- or aryloxyalkyl-acyl function, with an interesting subtype-selectivity profile, which makes them suitable candidates for their resolution as enantiomers structurally related to (+)-cyclazosin.
Subject(s)
Adrenergic alpha-1 Receptor Antagonists , Binding Sites/drug effects , Quinazolines/chemical synthesis , Quinazolines/pharmacology , Quinoxalines/chemical synthesis , Quinoxalines/pharmacology , Animals , Binding Sites/genetics , Binding Sites/physiology , CHO Cells/drug effects , Clone Cells/drug effects , Cricetinae , Guinea Pigs , Humans , Male , Prazosin/pharmacology , Rats , Receptors, Adrenergic, alpha-1 , Spleen/drug effects , Vas Deferens/drug effectsABSTRACT
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.
Subject(s)
Dioxolanes/chemistry , Dioxolanes/pharmacology , Muscarinic Antagonists/chemistry , Muscarinic Antagonists/pharmacology , Animals , Dioxolanes/chemical synthesis , Guinea Pigs , Ileum/drug effects , Ileum/metabolism , Magnetic Resonance Spectroscopy , Male , Models, Molecular , Molecular Structure , Muscarinic Antagonists/chemical synthesis , Myocardium/metabolism , Rabbits , Structure-Activity Relationship , Vas Deferens/drug effects , Vas Deferens/metabolismABSTRACT
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.
Subject(s)
Dioxolanes/chemical synthesis , Muscarinic Antagonists/chemical synthesis , Sulfones/chemical synthesis , Sulfoxides/chemical synthesis , Animals , Dioxolanes/chemistry , Dioxolanes/pharmacology , Guinea Pigs , Heart/drug effects , Ileum/drug effects , In Vitro Techniques , Male , Muscarinic Antagonists/chemistry , Muscarinic Antagonists/pharmacology , Rabbits , Receptor, Muscarinic M1 , Receptor, Muscarinic M2 , Receptor, Muscarinic M3 , Receptors, Muscarinic/drug effects , Structure-Activity Relationship , Sulfones/chemistry , Sulfones/pharmacology , Sulfoxides/chemistry , Sulfoxides/pharmacology , Vas Deferens/drug effectsABSTRACT
On the basis of an hypothesis according to which suitable nucleophilic agents may convert adenosine diphosphate (ADP) into adenosine monophosphate (AMP) and adenosine, well known inhibitors of ADP-induced platelet aggregation, some N-heterocyclic aldoxime methiodides were tested as inhibitors of ADP-induced rabbit platelet aggregation. Several 1-aryl-2-hydroxyiminomethly-3-methylimidazolium iodides significantly inhibit in vitro and in vivo-in vitro ADP-induced rabbit platelet aggregation.
Subject(s)
Heterocyclic Compounds/pharmacology , Oximes/pharmacology , Platelet Aggregation/drug effects , Adenosine Diphosphate , Animals , RabbitsABSTRACT
Methylation of the carbon atom C of compound 1, a potent and not selective muscarinic antagonist, was carried out. The resulting diastereomers were separated and the corresponding racemate further resolved to give four enantiomers, which were tested both as hydrogen oxalate and methiodide salts. The pharmacological results obtained at M1, M2 and M3 muscarinic receptor subtypes, show that methylation at C1, depending on the stereochemistry, increases antagonist potency, having thus the same effect of nitrogen quaternization. These results may well lead to the development of new potent antimuscarinic drugs lacking a cationic head.