Non-methylated Compounds Research Articles

Immobilized Organo-Mercurial Lyase on Zeolite Using a Solid Binding Peptide

Methylmercury (MeHg) compounds can form naturally, are highly toxic, and of concern because of their tendency to bio-accumulate. Certain bacteria have evolved mechanisms that can tolerate MeHg by first demethylating MeHg compounds, before further processing. Drawing inspiration from this demethylation mechanism controlled by a single organo-mercurial lyase in a protonolysis reaction, this research uses a recombinant gene that produces this lyase plus an additional polypeptide that selectively binds to zeolite particles, effectively tethering the enzyme to the solid substrate. This work is part of a broader attempt to create a fixed bed reactor for de-methylation of MeHg. Enzyme immobilization was achieved using a solid binding peptide (SBP) with high affinity for faujasite zeolite (FZ), the choice of binding substrate in the present work. The lyase is coded for by the merB gene, and a sequence with highly conserved active site homology was obtained from E.coli plasmid R8361b. The SBP plus merB sequence was designed such that the SBP was positioned either on the N or C-terminal of the construct. The DNA was synthesized commercially, and expressed in E.coli (BL21DE3 Star) using pET100® vector. Sanger sequencing was used to confirm construct in transformed cells using standard T7 oligos. Expression was lactose induced, and SDS-PAGE electrophoresis was used to confirm protein production and size. LC-MS/MS and sequence bio-analytics confirmed peptide sequence. Silica binding assays using SDS-PAGE confirmed binding of the enzyme to the silica substrate. Enzyme functionality results using a non-methylated mercuric compound were inconclusive, however the enzyme has not been assessed using MeHg compounds at this stage.

Alanine Counteracts the Destabilizing Effect that Urea has on RNase-A.

It is generally believed that organisms use and accumulate methylamine osmolytes to prevent urea's damaging effect on protein stability and activity. However, urea-rich cells not only accumulate methylamines but also many other methylated and non-methylated compounds as well. But, so far it is not known whether osmolytes that are not accumulated in urea-rich cells could also confer urea-counteracting properties. We investigated the behavior of a non-methylamine osmolyte, alanine for its counteracting effect against urea denaturation of a model protein, ribonuclease A (RNase-A). We have measured structure and thermodynamic parameters (Tm, ΔHm, and ΔGD°) of RNase-A in the presence of alanine, urea and their combination. The results were also compared with the ability of glycine (osmolyte lacking one methyl group when compared with alanine) to counter urea's effect on protein stability. We observed that alanine but not glycine counteracts urea's harmful effect on RNase-A stability. The results indicated that alanine (in addition to methylamine osmolytes) may serve as an alternate urea-counteractant. Since glycine fails to protect RNase-A from urea's destabilizing effect, it seems that methylation to glycine might have some evolutionary significance to protect proteins against harmful effects of urea.

Synthesis, Antitubulin, and Antiproliferative SAR of C3/C1‐Substituted Tetrahydroisoquinolines

The syntheses and antiproliferative activities of novel substituted tetrahydroisoquinoline derivatives and their sulfamates are discussed. Biasing of conformational populations through substitution on the tetrahydroisoquinoline core at C1 and C3 has a profound effect on the antiproliferative activity against various cancer cell lines. The C3 methyl-substituted sulfamate (±)-7-methoxy-2-(3-methoxybenzyl)-3-methyl-6-sulfamoyloxy-1,2,3,4-tetrahydroisoquinoline (6 b), for example, was found to be ∼10-fold more potent than the corresponding non-methylated compound 7-methoxy-2-(3-methoxybenzyl)-6-sulfamoyloxy-1,2,3,4-tetrahydroisoquinoline (4 b) against DU-145 prostate cancer cells (GI50 values: 220 nM and 2.1 μM, respectively). Such compounds were also found to be active against a drug-resistant MCF breast cancer cell line. The position and nature of substitution of the N-benzyl group in the C3-substituted series was found to have a significant effect on activity. Whereas C1 methylation has little effect on activity, introduction of C1 phenyl and C3-gem-dimethyl substituents greatly decreases antiproliferative activity. The ability of these compounds to inhibit microtubule polymerisation and to bind tubulin in a competitive manner versus colchicine confirms the mechanism of action. The therapeutic potential of a representative compound was confirmed in an in vivo multiple myeloma xenograft study.

Structures of cyclic dipeptides: an X-ray and computational study of cis- and trans-cyclo(Pip-Phe), cyclo(Pro-Phe) and their N-methyl derivatives

The crystal structures of eight cyclodipeptides are determined, incorporating pipecolic acid or proline and phenylalanine or N-methyl phenylalanine. This set of structures allows the evaluation of the effects on molecular conformation and crystal packing of imino acid ring-size, relative configuration of the two amino acids, and N-methylation. In the non-methylated compounds, hydrogen-bonding interactions form one-dimensional motifs that dominate the packing arrangement. Three compounds have more than one symmetry-independent molecule in the asymmetric unit (Z' > 1), indicative of a broad and shallow molecular energy minimum. Density functional theory calculations reveal the interplay between inter- and intramolecular factors in the crystals. Only for the N-methylated compounds do simulations of the molecules in the isolated state succeed to reproduce the observed crystallographic conformations. Puckering of the diketopiperazine ring and the deviation from planarity of the amide bonds are not reproduced in the remaining compounds. Cluster in vacuo calculations with a central cyclodipeptide molecule surrounded by hydrogen-bound molecules establish that hydrogen bonding is of major importance but that other intermolecular interactions must also contribute substantially to the crystal structure. More advanced periodic calculations, incorporating the crystallographic environment to the full extent, are necessary to correctly describe all the conformational features of these cyclodipeptide crystals.

Synthesis and Self-Assembly of Galactose-Terminated Alkanethiols and Their Ability to Resist Proteins

The synthesis of two galactose-terminated alkanethiols with the structural formula X-OC2H5NHCO(CH2)15SH (X = 2,3,4,6-tetra-O-methyl-beta-D-Gal or beta-D-Gal) is described. Single-component and mixed self-assembled monolayers (SAMs) of the methylated and nonmethylated compounds were prepared on gold and subsequently characterized with ellipsometry, contact angle goniometry, and infrared reflection-absorption spectroscopy. Studies of the irreversible protein adsorption onto the SAMs using ex-situ ellipsometry revealed very low levels of fibrinogen and lysozyme adsorption onto mixed SAMs displaying advancing water contact angles between 24 degrees and 45 degrees and below 45 degrees , respectively. A monomethylated compound (X = 6-O-methyl-beta-D-Gal) was also synthesized and assembled on gold. This particular compound was found to possess wettability properties corresponding to the low adsorption regime of the mixed SAMs, and the results from the same set of fibrinogen and lysozyme adsorption experiments showed very low levels of protein adsorption. Our findings suggest that the protein rejecting properties rely on a fine balance between the surface energy and/or hydrogen bond donating/accepting properties of the SAM surface.

Exploring potential energy hypersurfaces for triple symmetric inversion in 3-azabicyclo[3.3.1]nonan-9-one and itsN-methyl derivative

The potential energy hypersurfaces for the triple inversion, from chair to boat and α to β conformations, are explored theoretically in 3-azabicyclo[3.3.1]nonan-9-one and its N-methyl derivative, by using ab initio quantum-mechanical calculations. Both compounds are precursors of rigid analogs of the potential GABAA and GABAB receptor antagonists. In contrast to results from semiempirical calculations, the chair–chair β conformers are found to be, by far, the most stable structures for both the nonmethylated and N-methylated compounds. The inversion barriers are found to be relatively low, so that the conformers could be expected to exist in thermodynamic equilibrium at room temperature. A population analysis reveals, however, that, in the ab initio approach, the molecules seem to exist practically only in the chair–chair–β conformation. The theoretical results compare well with the available experimental data. © 1998 John Wiley & Sons, Inc. J Comput Chem 19: 1567–1574, 1998

Evaluation of cannabimimetic effects of structural analogs of anandamide in rats

Arachidonylethanolamide (anandamide), an endogenous ligand for the cannabinoid receptor, binds competitively to brain cannabinoid receptors and shares many, but not all, of the in vivo effects of Δ 9-tetrahydrocannabinol. In this study, the cannabinoid effects of anandamide analogs in which the anandamide molecule was altered were assessed in a drug discrimination model. Structural manipulations of the anandamide molecule included saturation of the arachidonyl moiety with fluorination (O-586), substitution for either the ethanolamide moiety (O-612 and O-595) or C2′ hydroxyl (O-585), and addition of a methyl group at various positions (O-610, O-680, and O-689). Despite the low binding affinities of the non-methylated compounds ( K i values >2000 nM), all of the analogs had previously shown cannabinoid activity in mice. In the present study, these analogs were tested in a more pharmacologically specific Δ 9-tetrahydrocannabinol discrimination procedure in rats. This animal model is predictive of the subjective effects of marijuana intoxication in humans. Whereas Δ 9-tetrahydrocannabinol and an aminoakylindole fully substituted for the training dose of 3 mg/kg Δ 9-tetrahydrocannabinol, anandamide and its non-methylated analogs were not cannabimimetic in this procedure. Methylation appeared to increase binding affinity ( K i values <150 nM) and efficacy; however, the greatest substitution produced by the methylated analogs occurred only at doses that decreased overall rates of responding, suggesting that these analogs are not fully Δ 9-tetrahydrocannabinol-like. The rapid metabolism of anandamide and some of its analogs undoubtedly contribute to the differences between the pharmacological profiles of the anandamides and classical cannabinoids. These results support the prediction that the subjective effects of anandamide analogs that have been developed thus far would not be cannabimimetic except at high doses.

Photocatalytic oxidation of phenolic compounds in wastewater from oil shale treatment

Experimental research into the photooxidation of aqueous solutions and wastewaters containing phenolic compounds was undertaken. Titanium dioxide under near-UV irradiation was selected as a photocatalyst. Phenol, p-cresol, resorcinol and 5-methylresorcinol (5-MR) were chosen as model compounds for the experiments with synthetic phenolic solutions. The photooxidative treatment of phenolic solutions was found to be more effective in acidic and strongly alkaline media. No difference was found between shortwave and near-UV irradiation photooxidation abilities. Methylated phenolic substitutes (p-cresol, 5-MR) yield better to photooxidation than non-methylated compounds. The higher the irradiation intensity the lower the photooxidation efficiency. The results obtained from the experiments with model compounds were compared with the results of photooxidative purification of wastewaters produced from the thermal treatment of oil shale in Estonia. Being heavily polluted, the wastewater yields better to photooxidation when slightly diluted with potable water in a 3:1 ratio. Anatase, immobilised onto the surface of buoyant hollow glass microspheres, was less effective than when suspended in a slurry. The photooxidatively pre-treated wastewater showed better biodegradability and lower toxicity to bacteria than untreated wastewater.

Photocatalytic oxidation of phenolic compounds in wastewater from oil shale treatment

Experimental research into the photooxidation of aqueous solutions and wastewaters containing phenolic compounds was undertaken. Titanium dioxide under near-UV irradiation was selected as a photocatalyst. Phenol, p-cresol, resorcinol and 5-methylresorcinol (5-MR) were chosen as model compounds for the experiments with synthetic phenolic solutions. The photooxidative treatment of phenolic solutions was found to be more effective in acidic and strongly alkaline media. No difference was found between shortwave and near-UV irradiation photooxidation abilities. Methylated phenolic substitutes (p-cresol, 5-MR) yield better to photooxidation than non-methylated compounds. The higher the irradiation intensity the lower the photooxidation efficiency. The results obtained from the experiments with model compounds were compared with the results of photooxidative purification of wastewaters produced from the thermal treatment of oil shale in Estonia. Being heavily polluted, the wastewater yields better to photooxidation when slightly diluted with potable water in a 3:1 ratio. Anatase, immobilised onto the surface of buoyant hollow glass microspheres, was less effective than when suspended in a slurry. The photooxidatively pre-treated wastewater showed better biodegradability and lower toxicity to bacteria than untreated wastewater.

Bay-region distortions in a methanol adduct of a bay-region diol epoxide of the carcinogen 5-methylchrysene.

The three-dimensional structure of the product of the reaction of a diol epoxide of the carcinogen 5-methylchrysene with methanol has been determined by an X-ray diffraction analysis. The diol epoxide used to obtain this compound contains a stereochemically hindered bay region because of the location of the 5-methyl group, and this might be expected to affect the type of chemical reaction that occurs. The crystal structure analysis of this adduct of a polycyclic aromatic hydrocarbon (PAH) showed that a methoxy group has been added at the carbon atom of the epoxy group that is nearest to the aromatic system. The bond that is formed is axial to the ring system so that the carbon and hydrogen atoms of the methoxy group are considerably displaced from the PAH ring plane. The bay-region methyl group at position 5 is displaced out of the ring plane in the opposite direction. The major steric distortion in this methanol adduct is shown, by a comparison with crystal structures of related non-methylated compounds, to be in the area of the 5-methyl group and not in the tetrol-bearing ring. The steric effects that caused the axial conformation of the newly formed bond would also be expected to pertain in the DNA adduct of a PAH with a bay-region methyl group. Since the presence of the bay-region methyl group in 5-methylchrysene has been shown to enhance the carcinogenicity of this PAH over the parent compound or compounds with methyl groups in other positions of the molecule, it might be anticipated that this axial bond is found in carcinogenic lesions in DNA, and that any factor that ensures this axial conformation may accentuate the carcinogenic potential of a PAH of the appropriate size.

Exploring the potential energy hypersurfaces for the triple symmetric inversion in 3-azabicyclo[3.3.1]nonan-9-one and its N-methyl derivative

The potential energy hypersurfaces for the triple inversion, from chair to boat and α to β conformations, are explored theoretically, by using the quantum semiempirical method AM1, in 3-azabicyclo[3.3.1]nonan-9-one and its N-methyl derivative. Both compounds are precursors of rigid analogues of the potential of γ-butyric acid receptor antagonists (GABA B). It is found that the chair—chair α conformer is by far the most stable structure for the non-methylated compound. In contrast, N-methylation changes the conformational preference to the β structure, the chair—chair β conformer being the most stable. The inversion barriers are calculated to be relatively low, so that the conformers must be found in thermodynamic equilibrium. The theoretical results compare well with the available experimental results.

Pharmacokinetics of Gyrase Inhibitors, Part 1: Basic Chemistry and Gastrointestinal Disposition

This review describes the physicochemistry and pharmacokinetic principles of gyrase inhibitors in relation to their distribution in the gastrointestinal tract. Their basicity and lipophilicity at physiologic pH, which affect their disposition in the gastrointestinal tract, are weakened or strengthened by substitutions on the quinoline nucleus. Heterocyclic substitution at position 7 significantly increases basicity and affects lipophilicity considerably. At physiologic pH, the 3-carboxyl group adds significant negative charge. The balance between the negatively charged carboxyl group and the positively charged heterocycle substitutions determines the pH-dependent ratio between ionized and un-ionized species and the solubility and lipophilicity of gyrase inhibitors. After oral administration, both the maximal plasma concentration (Cmax) and time to reach this value (Tmax) are affected primarily by the absorption constant. Absorption of N4'-methylated gyrase inhibitors tend to be greater than that of nonmethylated compounds. Acid-base properties affect absorption as do solubility and dissolution rates. Gyrase inhibitors probably are absorbed primarily in the upper gastrointestinal tract. Food does not alter overall absorption of several gyrase inhibitors studied but prolongs the Tmax slightly but significantly. N4'-methylation appears to protect against effects of food. Delay in gastric emptying may cause the increase in Tmax of gyrase inhibitors ingested with fatty meals. Effects of antacids on absorption of gyrase inhibitors depend on the interval between administration. Other ions also may reduce the absorption of gyrase inhibitors, but histamine-2 (H2)-antagonists appear to affect intestinal absorption of some, but not all, gyrase inhibitors. Gyrase inhibitors undergo significant gastrointestinal elimination.

Stability of premethylated aromatic model compounds of constituents of humic substances toward KMnO 4 oxidation

When analyzing aromatic constituents of humic substances, should potassium permanganate (KMnO 4) be used directly for the release of these constituents, aromatic rings possessing hydroxyl groups may easily be decomposed. As a means for stabilizing these compounds, methylation before KMnO 4 oxidation (premethylation) was conducted and the results were investigated. 28 different aromatic model compounds having hydroxyl and/or carboxyl groups were used as aromatic model compounds of constituents of humic substances. The recovery of these compounds and their methylated compounds after KMnO 4 oxidation was assessed quantitatively. The reaction temperature of KMnO 4 oxidation was 50°C. In the oxidation of non-methylated compounds, those having at least one hydroxyl group were easily decomposed by KMnO 4 oxidation, but for those with only a carboxyl group, stability was retained, except for terephthalic acid. In the oxidation of methylated compounds, many of those possessing carboxyl and hydroxyl groups could be stabilized by methylation, while those possessing only the hydroxyl group or substituted by two hydroxyl groups at the mutually meta- and para-positions with no intervening substitution groups, easily underwent decomposition even if methylated. Assessment of the applicability of the premethylation technique was made for more complex compounds. Two tannic compounds, (+)-catechin and penta-G-glucose, were used for this purpose, since their chemical structures are well known. Following premethylation, they were decomposed by KMnO 4 and then remethylated by dimethyl sulfate and potassium carbonate. GC/MS was used for the analysis of oxidation products. Compounds which could be predicted from the structure of original compounds were obtained in high yields.

Determination of methylmercury in human blood using capillary gas chromatography and selected-ion monitoring

A capillary gas chromatographic method, using selected-ion monitoring in the electron-impact mode, was developed for the analysis of methylmercury (MeHg) in human blood. The samples, spiked with the internal standard propylmercury bromide (PropHgBr), were, after addition of sodium bromide and cupric sulfate, extracted with toluene. The organic phase was extracted with an ethanol—water solution of sodium thiosulfate. After addition of sodium bromide solution, the ethanol—water phase was extracted with toluene. Methylated derivatives (MeHgCH 2Br and PropHgCH 2Br) were formed by the addition of a diethyl ether solution of diazomethane. The chromatographic properties of the derivatives were much better than those of the non-methylated compounds. The m/z 215 fragment of MeHgCH 2Br and the molecular ion m/z 338 of PropHgCH 2Br were monitored. The calibration graphs, with a linear correlation coefficient of 0.992 ( n = 12) in the 1–5 μg/l concentration range, passed through the origin. The detection limit for MeHg in human blood was ca. 0.5 μg/l. Analysis of spiked blood samples at concentrations of about 2 and 10 μg/l gave a relative standard deviation of 4.2 and 5.5%, respectively ( n = 10).

Omega-oxidized leukotriene B4 detected in the broncho-alveolar lavage fluid of patients with non-cardiogenic pulmonary edema, but not in those with cardiogenic edema

Leukotriene (LT) generation has been implicated in the pathogenesis of the acute respiratory distress syndrome, ARDS. In the present study, we analysed broncho-alveolar lavage fluids of patients on mechanical ventilation because of ARDS (17 samples taken from 9 patients) or because of cardiogenic edema (8 samples taken from 6 patients) and of healthy volunteers (10 samples from different donors). LTs were separated as methylated and non-methylated compounds using different HPLC procedures, and were identified by chromatographic mobility, on-line UV-spectrum analysis and post HPLC immunoreactivity. In the lavage samples of the healthy volunteers and the patients with cardiogenic edema, no LTs were detected by these techniques (detection limit congruent to 0.1-0.2 ng/ml lavage fluid). By contrast, in 15 out of 17 samples from patients with ARDS LTB4 or its metabolites 20-OH-LTB4 and 20-COOH-LTB4 were detected. The endproduct of omega-oxidation, 20-COOH-LTB4, represented the quantitatively predominant compound, detected in the range of 0.3-2.6 ng/ml perfusate. We conclude that the chemotactic agent LTB4 may be involved in the amplification of inflammatory events encountered in ARDS, and that the oxidized metabolites of LTB4 are particularly suitable for monitoring lung leukotriene generation under conditions of neutrophil efflux and oxidative stress.

Conformationally constrained D,L-alternating oligopeptides.

The possibility of selectively reducing the number of beta-helical structures theoretically possible for a D,L-alternating peptide by using a N-methyl group as conformational constraint is considered. Some 1H-nmr data regarding Boc(L-Nle-D-Nle)3-L-Nle-D-MeNle-L-Nle-D-Nle-L-Nle-OMe (I), its formyl analogue (II), and the pentadecapeptide Boc(D-Leu-L-Leu)5-D-MeLeu-(L-Leu-D-Leu)2-OMe (III) are presented. It is shown that these alternating stereocooligopeptides with a N-methyl group in the (n - 3) (I and II) or (n - 4) position (III) differ drastically in their behavior from the corresponding nonmethylated compounds. In chloroform, I and II form predominantly -- beta 7.2-helices and III forms almost exclusively -- beta 5.6 or -- beta 7.2-helices. The helices are in every case those having the maximum possible number of interchain H bonds.

The molecular gas phase structure of Tl( 5Me 5)

The thermal average molecular structure of Tl(C 5Me 5) has been determined by gas phase electron diffraction (GED). The molecule has a half sandwich structure of C 5 v symmetry. The TlC bond distance is 266.3(5) pm, with a root-mean-square amplitude of vibration ( l-value) of 5.2(24) ppm. The results indicate that the methyl groups of the ring tend to decrease the thalliumcarbon bond distance compared with that in the non-methylated compound.

Action of PGI 2 analogs on the pulmonary and systemic circulations in the conscious newborn lamb

Previous work (Lock et al. , J. Pharm. Exp. Ther. 215 :156, 1980) has shown that conventional screening procedures for vasoactive PGI 2 analogs have little value in predicting pulmonary vasodilator activity in the newborn lamb. To gain a better insight into the structural requirements for pulmonary vasoactivity and possibly identify useful compounds for the management of neonatal pulmonary hypertensive disorders, we have tested the following PGI 2 analogs in normoxic and hypoxic newborn lambs: 15(S)-9-deoxy-15-methyl1–9α, 6-nitrilo-PGF 1 (analog I); 9-deoxy-9α, 5-nitrilo-PGF 1 (analog II); (6S, 15S)-15-methyl-PG1 1 (analog III); and (6R, 15S)-15-methyl-PGI 1 (analog IV). A prostaglandin analog mimicking PGI 2 (compound BW245C; (±)-5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl)hydantoin) was tested as well. Compounds were injected into a branch pulmonary artery and any local pulmonary effect could be assessed from the change in the ratio of blood flow to the injected lung over total flow. None of the analogs tested proved to be a selective pulmonary dilator. BW245C was a potent peripheral vasodilator (threshold around 0.5 μg/kg) and indirectly lowered pulmonary vascular resistance through its systemic effects. Analog I also dilated the systemic circulation, but only at the highest dose tested (100 μg/kg). The latter finding is surprising because it was previously shown that the parent, non-methylated compound is a fairly potent and selective pulmonary vasodilator. Analog II and IV were inactive at a dose up to, respectively, 30 and 20 μg/kg. Analog III, on the other hand, weakly constricted the systemic circulation at a dose of 10 μg/kg. These findings suggest that the neonatal pulmonary vasculature is endowed with specific receptor sites which can discriminative between closely related PGI 2 analogs.

Testicular effects of some xanthine derivatives in the rat.

Testicular toxicity as well as effects on body weight gain and food consumption of four xanthine derivatives were studied in the Sprague-Dawley rat. The influence on toxicity by variation of the substituent at positions 1 and 3 on the xanthine skeleton was tested. The compounds were administered orally once a day for 1 month. The 1-methylated xanthines seemed to be more toxic than the non-methylated compounds.

On the pharmacology of α-methylated catecholamines and the mechanism of the antihypertensive action of α-methyldopa

The “false transmitter hypothesis” as put forward by Day and Rand (1) explains the blood pressure lowering action of α-methyldopa in hypertension by the partial replacement of the physiological transmitter noradrenaline (Nor) by the weaker vasoconstrictor α-methylnoradrenaline (α-MNor). The hypothesis was favored by the finding that sympathetic nerves of animals pretreated with α-methyldopa contained α-MNor (2,3,4), and that the α-methylated catecholamine was released on electrical nerve stimulation (5,6). However, even when the Nor of the sympathetic nerves was quantitatively replaced by α-MNor it was not possible to demonstrate substantially weaker responses of target organs to electrical nerve stimulation (7,8,9). Indeed, contrary to Day and Rand (8), other authors found Nor and α-MNor equally potent in the cat and rat blood pressure (3,9,10). Furthermore, there was a lack of correlation between the time course of the blood pressure lowering and the Nor replacing effect of α-methyldopa: at the time of maximal depletion and replacement of Nor by α-MNor the lowered blood pressure had already returned to its original level (11,12). On the other hand it is well established that α-methyldopa must be decarboxylated to exert its hypotensive action (11,13). Therefore, the blood pressure lowering effect may be correlated to the phase in which α-methyldopamine (α-MDop) originates from α-methyldopa by decarboxylation. Being a rather poor vasoconstrictor and partial agonist it occupies the adrenergic α-receptors, thus preventing Nor to react with them (14). It seemed worthwhile to investigate further the pharmacological potency of the α-methylated catecholamines in comparison with their non-methylated compounds, i.e. , their intrinsic activities and affinities for α- and ß-receptors.