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M S Verlander

Publications and source records attributed to M S Verlander.

18 recordsLinked to original sources
PubMed1987

In vitro pharmacologic activity of congener derivatives and model conjugates of propranolol and practolol.

Previous studies in our laboratory suggested that synthetized derivatives of isoproterenol and histamine could create agonists more potent and receptor and/or tissue selective than the parent compound. In the present study we have evaluated the hypothesis that our results with isoproterenol and histamine derivatives could be extended to include beta-adrenergic antagonists. With this purpose in mind, fourteen derivatives of propranolol and practolol were synthesized and tested in four in vitro systems. The congeners and conjugates were tested using biologic assays (blocking of cAMP accumulation) and/or radioligand binding assays in S-49 lymphoma cells and in rat adipocytes, heart and lung which contain beta 1 and/or beta 2 receptors. Our results indicate that structural modifications distant from the pharmacophore alter the pharmacologic profile of the parent compound. The relative potencies of the derivatives were dependent upon several key factors including the length of the methylene spacer chain and the nature of the substituents on the aromatic ring. The presence of a spacer group with four methylenes resulted in the most active compound in each series when tested on S-49 cells. The derivatives with a paramethyl toluidide group were more potent than the derivatives with a trifluoromethyl toluidide group. The dipeptide derivatives were more potent on adipocyte than S-49 cells, suggesting a preference for beta 1 receptors. Some of the same modifications that led to altered potency and which resulted in an increased receptor and/or tissue selectivity using the progenitors isoproterenol or histamine did extrapolate to the beta blockers. Our data suggest that alterations in receptor and/or tissue selectivity must be imparted by the carrier moiety of the drug and may be related to the biochemical microenvironment of the receptors.

Adipose Tissue↗
PubMed1987

Congener derivatives and conjugates of histamine: synthesis and tissue and receptor selectivity of the derivatives.

A series of 19 congener derivatives and conjugates of histamine was synthesized and tested to determine whether the ligands would alter the conventional histamine activity in various tissues. The derivatives, which contained either branched or unbranched aliphatic groups, aromatic amide groups, or dipeptides, exhibited affinities for histamine type 1 and/or type 2 receptors that were widely different from the progenitor. The p-trifluoromethyl derivative of histamine with an intermediate chain length of four methylenes (compound 13) was the most potent lymphocytes H2 receptor agonist but was inactive on guinea pig myocardium H2 receptors. The deletion of a single methylene chain (compound 12) from this compound resulted in total loss of its H2 activity on lymphocytes and its H1 activity on aorta. Compound 12 became an exclusive H1 agonist on lymphocytes H1 receptors. The dipeptide conjugate (compound 17) and the aliphatic congener derivative (compound 18), both with four methylenes, retained some of the activity on guinea pig myocardium H2 receptors, but lost their activity on lymphocytes H2 receptors. Therefore, histamine can be modified at sites that are at a distance from the imidazole moiety, resulting in tissue selective histamine receptor agonists.

Animals↗
PubMed1986

High potency congeners of isoproterenol. Binding to beta-adrenergic receptors, activation of adenylate cyclase and stimulation of intracellular cyclic AMP synthesis.

The potency of a p-toluide derivative and a p-trifluoromethyl derivative of isoproterenol on the beta1 receptor of turkey erythrocytes and on the beta2 receptor of S49 lymphoma cells was measured in comparison with isoproterenol. Binding assays showed that the p-trifluoromethyl derivative possessed an affinity for the receptor, which was two hundred times higher than that of isoproterenol, in the case of turkey erythrocytes, and sixty times higher in the case of the S49 cells. By measuring the Kact of adenylate cyclase, the activity of the p-trifluoromethyl derivative was thirty to forty times higher than that of isoproterenol for the turkey erythrocyte membrane as well as for the S49 lysed cells. In stimulation of intracellular cyclic AMP accumulation, the Kact showed that the p-trifluoromethyl derivative was forty and twenty times more active than isoproterenol in turkey erythrocytes and in S49 cells, respectively. The p-toluide derivative gave similar results. The superior affinity of the above isoproterenol congeners for both beta 1 and beta 2 adrenergic receptors makes these compounds excellent candidates for use as labeled agonist ligands in studies of beta receptors. The possibility is discussed that the relatively large substituent on the amino group of the catecholamine congeners might perhaps bind to lipids associated with the receptor.

Adenylyl Cyclases↗
PubMed1986

The effects of derivatives of histamine on natural suppressor cells.

Histamine is an impressive modulator of immune functions at least via its effects on lymphoid cells. Its in vivo effects will not be used practically as long as they produce the profound cardiovascular and pulmonary effects for which the drug is known. A series of 13 congener derivatives and conjugates of histamine was constructed and was tested to investigate whether chemical alterations would result in pharmacologic actions on leukocytes that were more potent and effect specific than histamine. The new compounds, which contained spacer groups of varying lengths between ligand and carrier and with various aromatic modifying groups, showed potencies widely different from histamine when tested in natural suppressor cells. Some compounds showed selective effects on natural suppressor cells in that they were inactive on myocardial tissue, whereas other compounds were selectively active on the myocardium. Some compounds augmented the suppressive capacity of natural suppressor cells in mixed leukocyte reactions via H1 receptors. Our scheme might be more widely extrapolated to other low m.w. immune modulators in an attempt to make them lymphocyte specific. The data also encourage the in vivo testing of selected histamine analogues as selective modulators of immunity. Some of these modulators might be experimentally useful in vivo because they may lack actions in other tissues.

Adenylyl Cyclases↗
PubMed1985

Conjugates of catecholamines. 5. Synthesis and beta-adrenergic activity of N-(aminoalkyl)norepinephrine derivatives.

A novel series of N-aminoalkyl congeners and model derivatives of norepinephrine has been synthesized. Compounds that were structurally related to epinephrine were prepared from fully protected intermediates. Alternatively, isoproterenol-related compounds were synthesized via reductive amination of preformed methyl ketone derivatives with norepinephrine. The beta-adrenergic activities of these new compounds were assessed through measurement of intracellular cyclic AMP accumulation in S49 mouse lymphoma cells and displacement of iodocyanopindolol (ICYP) from membrane preparations. Congeners that contained an underivatized primary amine function exhibited virtually no activity in these assays. However, when this amine function was acylated (e.g., to an amide, carbamate, urea, sulfonamide, etc.), the products exhibited generally increased beta-adrenergic activity, which was, however, strongly dependent on the nature of the acylating group and also the length of the spacer. In particular, a benzyl carbamate derivative containing a branched, seven-carbon spacer group was 40 times more potent than isoproterenol in the in vitro S49 assay.

Adrenergic beta-Agonists↗
PubMed1985

Conjugates of catecholamines. 6. Synthesis and beta-adrenergic activity of N-(hydroxyalkyl)catecholamine derivatives.

A new series of catecholamines has been prepared in which the N-alkyl substituent of dl-epinephrine or dl-isoproterenol has been extended by a methylene chain terminated by a hydroxyl group or derived functionality (e.g., carbamate or ester). These functionalized catecholamines (congeners) and model compounds were prepared with the goal of eventual attachment to polymeric carrier molecules. The beta-adrenergic agonist activity of the derivatives was evaluated in vitro by measuring the intracellular accumulation of cyclic AMP in S49 mouse lymphoma cells and by the displacement of iodocyanopindolol (ICYP). A n-butylcarbamate derivative (compound 15) was the most active compound in this series with a potency 190 times greater than dl-isoproterenol in the S49 assay. The biological results indicate that minor modifications in structure in the N-alkyl substituent of the catecholamine can influence the pharmacologic activity.

Adrenergic beta-Agonists↗
PubMed1983

Conjugates of catecholamines. 1. N-alkyl-functionalized carboxylic acid congeners and amides related to isoproterenol.

A series of functionalized catecholamines (congeners) has been synthesized in which, formalistically, the N-isopropyl group of isoproterenol has been extended by a linear alkyl chain of varying length, terminated by a carboxy group or a substituted amide. The compounds were prepared generally via the reductive amination of norepinephrine with a keto acid or a preformed keto amide. An alternate synthesis of the model amide derivatives, involving activation of the carboxylic acid congeners and coupling with amines, was complicated in the case of short-chain derivatives by facile cyclization to lactams. In vitro evaluation of these compounds as potential beta-adrenergic agonists has shown that, while the carboxylic acid congeners have relatively low potencies, the model amide derivatives have potencies that are highly dependent on both the length of the alkyl chain and also the nature of the substituent on the amide. In general, aromatic amides are the most potent, although the nature and position of substituents on the aromatic group dramatically influences their potency. The implications of these studies, in terms of general beta-adrenergic drug design and also the attachment of the carboxylic acid congeners to carriers, are discussed.

Animals↗
PubMed1983

Conjugates of catecholamines. III. Synthesis and characterization of monodisperse oligopeptides conjugates related to isoproterenol.

A series of monodisperse oligopeptide conjugates related to the catecholamine, isoproterenol, has been synthesized. The peptide carrier molecules used were synthesized by stepwise and fragment condensation techniques and ranged in size from a single, blocked amino acid derivative to isomeric pentapeptides. The amino acid compositions and sequences of the carriers were chosen so as to provide specific information concerning the effects of molecular weight, hydrophilic/hydrophobic balance, charge, etc., on the biological activity of the final conjugates. The common point of attachment for the drug in all carriers was a p-aminophenylalanine residue. The peptide-catecholamine conjugates were prepared via the attachment of carboxyl-containing catecholamine congeners, to the peptide carriers by techniques described previously. The conjugates were purified rigorously by chromatographic techniques and characterized by high-field n.m.r. spectroscopy.

Catecholamines↗
PubMed1983

Conjugates of catecholamines. IV. In vitro and in vivo pharmacological activity of monodisperse oligopeptide conjugates.

Conjugates of low molecular weight amines with inert peptide carriers can be made to preserve some pharmacologic effects of the ligand. No previous studies of conjugates have systematically derivatized the ligand to optimize its activity or affinity to receptors; or have pharmacophores been selected for conjugation on the basis of their effects making them particularly interesting as ligands. Chemically pure and characterizable conjugates ranging from single blocked amino acid derivatives to isomeric pentapeptides were constructed and tested for beta adrenergic properties. Sixteen conjugates with varying water solubility, amino acid composition and sequence, charged groups and spacer length between ligand and carrier showed potencies and duration of action widely different from isoproterenol. In the in vitro S-49 mouse lymphoma assay a range of relative potencies (as compared to isoproterenol) from 10(-6) to 1 time as potent was obtained, whereas in the in vivo rat blood pressure assay these compounds were shown to be from one-fifth to 4 times as potent as isoproterenol. The most potent compound tested, Boc-Phe(NH)-Gly-NHCH3, was also tested in a guinea-pig atrial preparation as well as in an anesthetized cardiovascular dog preparation. The results indicated that the compound was approximately 3.5 times more potent in producing an inotropic response than isoproterenol. In some instances, ostensively trivial changes quite distant from the pharmacophores in amino acid sequence of the carrier made major changes in potency and efficacy of the compound.

Adrenergic beta-Antagonists↗
PubMed1983

Conjugates of catecholamines. II. In vitro and in vivo pharmacological activity of N-alkyl-functionalized carboxylic acid congeners and amides related to isoproterenol.

In this study, 10 congeners of isoproterenol were systematically synthesized and pharmacologically tested in both in vitro and in vivo systems. The aim was to produce compounds that were more potent and had effects different from those of the parent compound and that could ultimately be attached covalently to inert peptide carriers offering versatility in size, pK, and other physicochemical properties. The congeners synthesized were tested in the S49 mouse lymphoma assay for their ability to stimulate cyclic AMP accumulation and were shown to have potencies relative to isoproterenol ranging from 4 orders of magnitude less potent to 4 orders of magnitude more potent than isoproterenol in eliciting this response. Some of the congeners were also tested in a guinea pig isolated atrial preparation, a rat blood pressure assay, a guinea pig bronchodilation assay, and an anesthetized dog preparation. In these assays, the congeners were shown to have the same types of activities as in the S49 cell assay. The results of these studies indicate that structural modifications distant from the catecholamine moiety dramatically alter the pharmacological profile of the congeners versus the parent compound, resulting in a series of ligands with a wide range of activities.

Adrenergic beta-Antagonists↗
PubMed1981

Inactivation of purified human alpha 2-antiplasmin and purified human C1 inhibitor by synthetic fibrinolytic agents.

3-Hydroxypropyl flufenamide (Flu-HPA) is one of a series of flufenamic acid derivatives that enhances blood clot lysis in vitro. Studies of possible mechanisms of action of Flu-HPA were undertaken. The profibrinolytic activity of Flu-HPA in clot lysis assays was found to be dependent on plasminogen. The influence of Flu-HPA on the ability of purified alpha 2-antiplasmin to inhibit purified plasmin was studied. Plasmin activity was determined using 125I-fibrin plates or the spectrophotometric tripeptide substrate, Val-Leu-Lys-paranitroanilide. At Flu-HPA concentrations greater than 1 mM, the inhibitory activity of alpha 2-antiplasmin was abolished in a time-dependent and concentration-dependent manner. The influence of Flu-HPA on the ability of purified Cl inhibitor to inhibit purified plasma kallikrein and beta-Factor XIIa was also studied. Cl inhibitor activity was abolished by Flu-HPA at concentrations greater than 2 mM. Notably, Flu-HPA up to 60 mM did not affect the amidolytic activities of plasmin, kallikrein, or beta-Factor XIIa. Flu-HPA did not release enzyme activity from preformed complexes of either alpha 2-antiplasmin and plasmin of Cl inhibitor and kallikrein. A water-soluble derivative of flufenamic acid, N-flufenamyl-glutamic acid, also inactivated alpha 2-antiplasm and Cl inhibitor. This inactivation was shown to be reversible. These results indicate that synthetic fibrinolytic compounds such as flufenamic acid derivatives may promote fibrinolysis by directly inactivating alpha 2-antiplasmin and Cl inhibitor.

Blood Coagulation↗
PubMed1976

Biological activity of catecholamines covalently linked to synthetic polymers: proof of immobilized drug theory.

l-Isoproterenol was covalently coupled via an azo linkage to soluble copolypeptides of molecular weight 1500 and 10,000 containing an aromatic amine. The polymeric azo-isoproterenol derivatives were purified by gel chromatography which reduced contamination by the parent isoproterenol to undetectable levels (i.e., less than 0.01%) and by 6-aminoisoproterenol to less than 0.4%. Both polymeric isoproterenol derivatives were found to elicit positive chronotropic responses in isolated perfused guinea pig hearts. The mean effective doses (ED50S) for the 1500 and 10,000 molecular weight derivatives were within 1.3 and 2.0 orders of magnitude, respectively, of the ED50 of l-isoproterenol. The responses cannot be attributed to free isoproterenol because this drug could not be detected in our preparations. Neither can the observed biological activity be attributed to 6-aminoisoproterenol, since this compound's dose-response is shifted 3 orders of magnitude to the right of l-isoproterenol and 1-2 orders of magnitude to the right of the polymeric derivatives. Inotropic response decay times in isolated cat papillary muscles following washouts indicate that the polymer-bound drug does not diffuse into the muscle tissues. We feel that our findings demonstrate that under controlled conditions the catecholamines can retain biological activity while covalently bound to a polymeric support.

Animals↗