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Biomedical subjects

G L Grunewald

Publications and source records attributed to G L Grunewald.

At least 55 records · Page 3Linked to original sources
PubMed1982

Importance of the aromatic ring in adrenergic amines. 7. Comparison of the stereoselectivity of norepinephrine N-methyltransferase for aromatic vs. nonaromatic substrates and inhibitors.

Some nonaromatic analogues of amphetamine and alpha-methylbenzylamine were prepared and evaluated as competitive inhibitors of norepinephrine N-methyltransferase (NMT). All of the nonaromatic analogues were significantly more active than their aromatic counterparts [Ki for amphetamine = 740 microM; Ki for 1-cyclooctyl-2-aminopropane = 86 microM]. In order to determine if the aliphatic ring of these analogues bound to the same binding site as the phenyl ring of amphetamine and alpha-methylbenzylamine, the stereoselectivity of NMT toward the different compounds was determined. Stereochemical requirements for aromatic and nonaromatic inhibitors were similar (in all cases the S isomer was more potent at inhibiting NMT). The stereochemical preference expressed for phenylethanolamine substrates and corresponding nonaromatic analogues was also found to be the same; however, as the lipophilicity of the nonaromatic ethanolamine analogues was increased, a loss in both stereoselectivity and substrate activity occurred. The results presented here are consistent with an aromatic ring binding site that is part of, or bordered by, a large hydrophobic area. The larger, more hydrophobic nonaromatic phenylethanolamine derivatives are drawn into the hydrophobic area, which reduces side-chain hydroxy interactions necessary for substrate activity.

Amphetamines↗
PubMed1982

Directional probes of the hydrophobic component of the aromatic ring binding site of norepinephrine N-methyltransferase.

We investigated the directional nature of the bulk tolerance and hydrophobic binding in the aromatic ring binding region of the active site of norepinephrine N-methyltransferase (NMT) by comparing the substrate and inhibitor activities of m- and p-phenyl-substituted derivatives of amphetamine, phenylethanolamine, and alpha-methylbenzylamine. The para isomers of amphetamine and phenylethanolamine displayed significantly greater activities as inhibitor and substrate, respectively, than the meta isomers, which indicated that the bulk tolerance was near the para position. For benzylamines, the greatest inhibitory activity was observed for the meta isomer, demonstrating a significant difference in the binding requirements for phenylethylamines and benzylamines. These findings are consistent with a two-state model for the NMT active site that has been proposed elsewhere to account for its ability to bind both benzylamines and phenylethylamines in a fully extended side-chain conformation.

Amphetamines↗
PubMed1982

Probes of the active site of norepinephrine N-methyltransferase: effect of hydrophobic and hydrophilic interactions on side-chain binding of amphetamine and alpha-methylbenzylamine.

A series of omega-substituted analogues of amphetamine and alpha-methylbenzylamine were prepared and evaluated as inhibitors of norepinephrine N-methyltransferase (NMT). These included several alkyl side chain extended analogues (1-5), as well as the terminally hydroxylated derivatives phenylalanol (6a) and phenylglycinol (7a). None of the alkyl-substituted derivatives displayed appreciable activity as inhibitors; however, the hydroxylated analogues were up to twofold more potent than the parent compounds. The positive contribution of the side-chain hydroxy suggests that the terminal methyl group of the lead compounds is situated close to a hydrophilic area or hydrogen bonding functional group within the active site.

Amines↗
PubMed1982

Importance of the aromatic ring in adrenergic amines. 8. 2-(Aminomethyl)-trans-2-decalols as inhibitors of norepinephrine N-methyltransferase.

In an effort to determine the surface appearance of the hydrophobic ring binding region of the norepinephrine N-methyltransferase active site, we employed some trans-decalin analogues of 1-(aminomethyl)cycloundecanol (1), a potent NMT inhibitor. These analogues [axial and equatorial 2-(aminomethyl)-trans-2-decalol, 2 and 3] closely resemble a low energy "crown" conformation of 1. Both compounds were as potent as 1 at inhibiting NMT (Ki = 3.6, 5.6, and 3.8 microM for 1, 2, and 3, respectively), indicating that this conformation is most likely adopted within the active site in order to optimize contact with a flat hydrophobic area. None of the compounds showed significant substrate activity for NMT, a fact that is consistent with our proposed active site binding model.

Adrenal Glands↗
PubMed1982

Inhibitors of phenylethanolamine N-methyltransferase. 1. Effects of 2-cycloocytyl-2-hydroxyethylamine on rat brain and adrenal catecholamine content and blood pressure.

Acute administration of 2-cyclooctyl-2-hydroxyethylamine (CONH), a potent phenylethanolamine N-methyltransferase inhibitor, produced time- and dose-related reductions of blood pressure in spontaneously hypertensive rats (SHR). CONH did not affect the blood pressure of age-paired normotensive Wistar-Kyoto rats (WKY), or the heart rate of either animal group. CONH produced dose- and time-related reductions in epinephrine (Epi) levels in the hypothalamus and brainstem of both SHR and WKY. The drug also produced dose- and time-related reductions in hypothalamic and brainstem norepinephrine concentrations and elevations in dopamine and 3,4-dihydroxyphenylacetic acid concentrations in both SHR and WKY. CONH was about equally effective in reducing brain norepinephrine and Epi concentrations in both animal strains, but CONH was more effective in elevating brain dopamine and 3,4-dihydroxyphenylacetic acid concentrations in SHR than in WKY. Subchronic administration (3 days) of CONH produced a dose-related reduction in blood pressure in SHR, but had no affect on blood pressure in WKY. The changes in blood pressure in SHR were accompanied by a dose-related reduction in hypothalamic Epi concentrations, but the drug treatment produced no affect on the concentration of Epi in the brainstem. The results of this study suggest that brain Epi-containing neurons may be directly involved in the regulation of blood pressure or alternatively they may indirectly control cardiovascular function by modulating brain norepinephrine- and/or dopamine-neuronal activity.

Adrenal Glands↗
PubMed1982

Inhibitors of phenylethanolamine-N-methyltransferase. 2. Comparison of nonaromatic analogs of phenylethanolamines, 7,8-dichloro-1,2,3,4-tetrahydroisoquinoline (SKF-64139) and 2,3-dichloro-alpha-methylbenzylamine: effects on rat brain and adrenal catecholamine content and blood pressure.

Intraperitoneal injections of the phenylethanolamine N-methyltransferase inhibitors 2-cyclohexyl-2-hydroxyethylamine, 1-aminomethylcycloundecanol, 7,8-dichloro-1,2,3,4-tetrahydroisoquinoline and 2,3-dichloro-alpha-methylbenzylamine all lowered blood pressures in spontaneously hypertensive rats. The drugs did not affect the blood pressures of age-paired normotensive Wistar Kyoto rats or did the drugs alter the heart rates of either animal group. All of the phenylethanolamine N-methyltransferase inhibitors tested lowered hypothalamic epinephrine content which in spontaneously hypertensive rats could be correlated with the reduction in blood pressure. These data support the hypothesis that central nervous system epinephrine may play an important role in the regulation of blood pressure and in the genesis and/or maintenance of hypertension. The results also suggest the hypothesis that the blood pressure lowering effects of phenylethanolamine N-methyltransferase inhibitors may be mediated by their effects on hypothalamic epinephrine content.

Adrenal Glands↗
PubMed1982

Effects of phenylethanolamine N-methyltransferase inhibitors on rat brain catecholamine levels and body temperature.

Inhibitors of phenylethanolamine N-methyltransferase (PNMT) were found to reduce hypothalamic and brainstem epinephrine (Epi) content, as well as the body temperature of male Sprague-Dawley rats. In the drug-treated animals, the time course for reduction of body temperature was better correlated with the reduction in brainstem Epi content than with the reduction in hypothalamic Epi content. These results suggest that brainstem Epi neurons may be directly involved in the regulation of body temperature by activating the heat production center or by preventing heat loss.

Animals↗
PubMed1981

Importance of the aromatic ring in adrenergic amines. 6. Nonaromatic analogues of phenylethanolamine as inhibitors of phenylethanolamine N-methyltransferase: role of pi-electronic and steric interactions.

To probe the importance of pi-electronic and steric interactions of nonaromatic analogues of phenylethanolamine as inhibitors of phenylethanolamine N-methyltransferase (PNMT), a series of norbornane and norbornene ethanolamines was prepared and evaluated as inhibitors of PNMT (liquid chromatographic-electrochemical detector assay). Previous studies indicated a major importance of hydrophobic interaction of the ring moiety attached to the ethanolamine side chain, but a possible importance of pi-complex formation could have been obscured by conformational differences among the analogues. In this study, norbornane and norbornene substituted with an ethanolamine side chain at positions 1,2-exo, and 2-endo were prepared from the corresponding aldehydes by addition of trimethylsilyl cyanide (Me3SiCN) and lithium aluminum hydride reduction. The saturated (norbornane) analogues were two times more potent as inhibitors of the enzyme than were the norbornene analogues, thus suggesting that pi-complex formation is not an important contribution to binding and, as previously proposed, a hydrophobic interaction is the significant binding interaction of the ring moiety. The hydrophobic binding area has a critical size that requires the hydrophobic moiety to be of sufficient length (the bridgehead-substituted norbornane and norbornene ethanolamines being too "'short" for optimal binding). The 2-exo orientation of the ethanolamine side chain was preferred to the 2-endo orientation, supporting our earlier hypothesis that the ring moiety prefers to be oriented away from the side chain.

2-Hydroxyphenethylamine↗
PubMed1980

Conformationally defined aromatic amino acids. Synthesis and stereochemistry of 2-endo- and 2-exo-amino-1,2,3,4-tetrahydro-1,4-ethanonaphthalene-2-carboxylic acids (2-endo- and 2-exo-aminobenzobicycle[2.2.2]octene-2-carboxylic acids).

The synthesis of the title compounds 1a and 1b has been accomplished in good yield by conversion of ketone 3 to the corresponding hydantoins 4a and 4b via a Bucherer-Bergs reaction, followed by barium hydroxide hydrolysis. The stereochemical assignments of the intermediate hydantoins 4a and 4b and the ethyl ester hydrochlorides 5a and 5b were determined by H NMR analysis. Attempts toward the synthesis of 2-amino-1,4-dihydro-1,4-ethanonaphthalene-2-carboxylic acid isomers 2a and 2b utilizing the pathway discussed for 1a and 1b led only to products arising from a retro-Diels-Alder reaction. Preliminary screening of 1a and 1b as inhibitors of phenylalanine hydroxylase (PH) and phenylalanine decarboxylase (PAD) is also discussed. The use of the benzobicyclo[2.2.2]octene nucleus for the construction of conformationally defined analogues of important medicinal agents is rationalized, and the title compounds are compared to several other conformationally defined systems. The title compounds represent conformationally defined models of the lower energy conformations of alpha-methylphenylalanine.

Animals↗
PubMed1979

Quantitative structure-activity relationships for biguanides, carbamimidates, and bisbiguanides as inhibitors of Streptococcus mutans No. 6715.

Thirty-seven compounds, including 17 biguanides, 6 carbamimidates, and 14 bisbiguanides, were evaluated for potential antiplaque activity by measuring their minimum inhibitory concentrations [MIC (M)] against Streptococcus mutans no. 6715. Linear regression analysis was conducted with the log 1/MIC (M) values and log P, pi, sigma, and MR. The best correlation for the biguanides (r2 = 0.92) was obtained with log P and (log P)2. When the biguanides were included with the carbamimidates, essentially the same correlation (r2 = 0.91) was obtained with log P and (log P)2. The best correlation for the bisbiguanides (r2 = 0.70) was also obtained with log P and (log P)2. Use of an indicator variable (I) for the bisgiguanides allowed all three groups to be included in one equation, which accounted for over 87% of the variance in the data for inhibition of bacterial growth. These results from the classical parabolic model were also compared with those from the recently developed bilinear model.

Biguanides↗
PubMed1977

Quantitative structure-activity relationships for 5-substituted 8-hydroxyquinolines as inhibitors of dental plaque.

Fourteen 8-hydroxyquinolines were tested for antiplaque activity by measuring their minimum inhibitory concentrations [MIC (M)] against Streptococcus mutans No. 6715. Linear regression analysis was conducted with the MIC (M) values and hydrophobic (log P), electronic (beta, pKaOH, pKaN), and steric [molar refractivity (MR), molecular weight (mol wt)] parameters. The best correlation (r2 = 0.90) was obtained with MR, log P, and beta. The smaller the steric contribution of the 5-substituent, the more active the compound. The parent 8-hydroxyquinoline was the most active. The negative contribution toward activity by 5-substituents larger than hydrogen can be overcome by the positive contributions of groups that are lipophilic and electron withdrawing; for example, the 5-chloro derivative is as active as the parent 8-hydroxyquinolines.

Dental Plaque↗