Biomedical subjects

G L Grunewald

Publications and source records attributed to G L Grunewald.

At least 37 records · Page 2Linked to original sources

PubMed1989

Conformational and steric aspects of phenylethanolamine and phenylethylamine analogues as substrates or inhibitors of phenylethanolamine N-methyltransferase.

The conformational and steric aspects of binding to phenylethanolamine N-methyltransferase (PNMT; EC 2.1.1.28) for phenylethanolamine substrates and phenylethylamine inhibitors were probed with three conformationally defined analogues (11, 12, and 13) of phenylethylamine (1) and phenylethanolamine (6) containing the benzobicyclo[3.2.1]octane skeleton. The 2-aminotetralin (2AT) moiety in conformationally defined analogues 11, 12, and 13 exists in a half-chair conformation with an equatorial amino group. Although conformationally restricted phenylethylamine analogue 2AT (3, Ki = 6.8 microM) and conformationally restricted phenylethanolamine analogues (cis)- and (trans)-2-amino-1-tetralol (9, Km = 22 microM; Vmax = 0.15; 100 X Vmax/Km = 0.68; 10, Ki = 9.4 microM) are good ligands for PNMT, none of the analogues 11, 12, and 13 showed activity as a substrate of PNMT. The fact that 11 (Ki = 206 microM) is more potent than analogues 4 (Ki = 1296 microM) and 5 (Ki = 479 microM), with a half-boat 2AT moiety, suggests that PNMT preferentially binds the half-chair conformation of 2AT at the active site. This is consistent with previous findings that a fully extended conformation for the aminoethyl side chain of phenylethylamine inhibitors is optimal for PNMT binding. The reduced activity of 11, 12 (Ki = 1246 microM), and 13 (Ki = 3000 microM), compared with 2AT and (cis)- and (trans)-2-amino-1-tetralol (9 and 10) is consistent with a negative steric interference from the extra ethano bridge in 11, 12, and 13. The results from 11, 12, and 13, combined with previous findings, suggest that PNMT interacts better with relatively planar ligands.

2-Hydroxyphenethylamine↗

PubMed1988

Stereochemical aspects of phenylethanolamine analogues as substrates of phenylethanolamine N-methyltransferase.

Phenylethylamines and phenylethanolamines represent two major classes of ligands for the epinephrine synthesizing enzyme, phenylethanolamine N-methyltransferase (PNMT;EC 2.1.1.28). Phenylethylamines are usually competitive inhibitors and the isomers with the relative configuration as in (2S)-amphetamine (1) and (2S)-2-aminotetralin (3) are better inhibitors than their enantiomers. Phenylethanolamines are usually substrates of PNMT and the enzyme prefers the 1R isomers, such as (1R)-phenylethanolamine (5), in this class. Optically active norephedrines (7 and 8), norpseudoephedrines (9 and 10), and 2-amino-1-tetralols (13-16) were used to study the stereochemical requirements of phenylethanolamines for PNMT active site binding. Although the norephedrines (7 and 8) and the norpseudoephedrines (9 and 10) were poorer ligands for PNMT than were the 2-amino-1-tetralols (13-16), (1R,2S)-(-)-norephedrine (7) showed some activity as a PNMT substrate (Km = 1310 microM, Vmax = 0.22, 100 x Vmax/Km = 0.017). In the 2-amino-1-tetralols (13-16), the isomers with the 2S configuration (13 and 15) showed higher affinity to PNMT (13, Km = 4.5 microM; 15, Ki = 4.6 microM) and those with the 1R configuration (13 and 16) were substrates for the PNMT-catalyzed methyl transfer (13, Km = 4.5 microM, Vmax = 0.16, 100 x Vmax/Km = 3.6; 16, Km = 195 microM, Vmax = 0.12, 100 x Vmax/Km = 0.062); the combination of 1R and 2S configurations, such as in (1R,2S)-2-amino-1-tetralol (13), was required for a good substrate. These stereochemical requirements derived from the norephedrines (7 and 8), the norpseudoephedrines (9 and 10), and the 2-amino-1-tetralols (13-16) complement those for phenylethylamines (1-4) and for phenylethanolamines (5 and 6) and strongly suggest that phenylethylamine inhibitors bind to PNMT in the same orientation as do phenylethanolamine substrates.

Animals↗

PubMed1988

Anticonvulsant activities of phenyl-substituted bicyclic 2,4-oxazolidinediones and monocyclic models. Comparison with binding to the neuronal voltage-dependent sodium channel.

8,9-Dioxo-6-phenyl-1-aza-7-oxabicyclo[4.2.1]nonane (1) and 9,10-dioxo-7-phenyl-1-aza-8-oxabicyclo[5.2.1]decane (2), examples of anti-Bredt bicyclic 2,4-oxazolidinediones, were investigated as anticonvulsants in mice. Compound 2 was the more potent (anti-MES ED50 = 66 mg/kg), and its in vivo anti-MES effect was consistent with its in vitro potency of binding to the voltage-sensitive sodium channel (IC50 = 160 microM for the inhibition of binding of [3H]BTX-B), suggesting that 2 may be a new class I anticonvulsant. Several partial structures of 2, either monocyclic lactams or monocyclic 2,4-oxazolidinediones, were also evaluated in these assays, but no correlation was observed between sodium channel binding and anti-MES effects. A significant finding was that monocyclic 5-alkyl-5-phenyl-2,4-oxazolidinediones provided relatively potent, nontoxic, broad-spectrum anticonvulsants.

Animals↗

PubMed1988

Conformational preference for the binding of biaryl substrates and inhibitors to the active site of phenylethanolamine N-methyltransferase.

We have previously described regions of steric bulk tolerance in the aromatic-ring binding site of phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28) for phenylethanolamine substrates and alpha-methylbenzylamine inhibitors. For bound substrates, this region is located in the vicinity of the para position of the aromatic ring, while for bound alpha-methylbenzylamine inhibitors, it is located in the region complementary to the meta position. In the present study, we sought to determine the preferred conformation of the biaryl portion of (m-phenylphenyl)- and (p-phenylphenyl)ethanolamine (4 and 5, respectively) as well as for m-phenyl- and p-phenyl-alpha-methylbenzylamine (7 and 8, respectively) for PNMT active site interactions. Planar derivatives of 4, 5, 7, and 8 were obtained through the synthesis of 2-(1-fluorenyl)-2-hydroxyethylamine (9), 2-(2-fluorenyl)-2-hydroxyethylamine (10), 1-(1-fluorenyl)ethylamine (11), and 1-(2-fluorenyl)ethylamine (12). The four fluorene derivatives were examined for in vitro activity as substrates and inhibitors of the PNMT-catalyzed reaction. As in the case of 4, 5, 7, and 8, we have observed a positional preference for the alkylamine side chain with respect to the biphenyl skeleton present in 9-12. Thus, fluorenylethanolamine 10 ("p-biphenyl") displays a Michaelis constant (Km = 26 microM) that is approximately 10 times lower than that for 9 ("m-biphenyl", Km = 297 microM); in the alpha-methylbenzylamine inhibitors, fluorenyl derivative 11 ("m-biphenyl", Ki = 4.14 microM) is approximately 40 times better than 12 ("p-biphenyl", Ki = 185 microM) for in vitro inhibition of PNMT. In each case, conformational restriction of the biaryl system present in 4, 5, 7, and 8, such that the aromatic rings are coplanar, resulted in enhanced affinity for the PNMT active site. Thus, conformational restriction of ethanolamine 5 (Km = 82 microM) as in 10 (Km = 26 microM) and alpha-methylbenzylamine 7 (Ki = 89 microM) as in 11 (Ki = 4.14 microM) leads, in each case, to a stronger enzyme-ligand dissociable complex. These results, in conjunction with others from these laboratories, indicate that the PNMT active site beyond the zone that interacts with the central aromatic ring portion of phenylethanolamine substrates and alpha-methylbenzylamine inhibitors is essentially a flat, hydrophobic pocket.

Adrenal Glands↗

PubMed1988

Conformational requirements of substrates for activity with phenylethanolamine N-methyltransferase.

beta-Phenylethanolamines have long been known to be substrates for the enzyme that converts norepinephrine to epinephrine (phenylethanolamine N-methyltransferase, PNMT, EC 2.1.1.28). In an effort to determine which, if any, particular conformation of the aminoethyl side chain of phenylethanolamines is required for PNMT active site binding and catalysis, we have prepared and evaluated conformationally restricted phenylethanolamine analogues 8-10. The folded phenylethanolamine derivative 4-hydroxy-1,2,3,4-tetrahydroisoquinoline (8) is not a substrate and does not interact with the enzyme active site as an inhibitor as well as 1,2,3,4-tetrahydroisoquinoline (6). In the cyclic 2-aminotetralol systems, only cis-phenylethanolamine derivative 9 demonstrates activity as a PNMT substrate. The corresponding trans isomer 10 is not a substrate, in spite of enhanced active site interactions with respect to the parent analogue (2-aminotetralin, 4). Comparison of the inhibition constants for the folded (8,Ki = 175 microM) and extended (10,Ki = 9 microM) phenylethanolamine analogues strongly suggests that simultaneous binding of both the amino and hydroxyl functionalities to the PNMT active site requires an extended aminoethyl side chain conformation.

Indicators and Reagents↗

PubMed1988

Conformational and steric aspects of the inhibition of phenylethanolamine N-methyltransferase by benzylamines.

Compounds of the benzylamine (BA) class are potent inhibitors of phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28). Restriction of the aminomethyl side chain through its incorporation into a cyclic framework as in 1,2,3,4-tetrahydroisoquinoline (THIQ) or 2,3,4,5-tetrahydro-1H-2-benzazepine (THBA) results in enhanced potency as an inhibitor, suggesting a conformational effect in the binding of BAs to the active site; however, these ring systems still retain a high degree of flexibility. We have synthesized a series of conformationally defined analogues of benzylamine in order to probe the effect of conformation, as well as the influence of steric bulk, on PNMT inhibition by this class of ligands. In addition, 1-, 3-, and 4-methyl-substituted THIQs were synthesized and evaluated as flexible models for steric bulk tolerance about this ring system. Substitution by a methyl group on either benzylic position of THIQ results in diminished activity as a PNMT inhibitor; however, 3-methyl-THIQ shows enhanced activity as an inhibitor vs THIQ itself. Full conformational restriction of the BA side chain in analogues 4-8 results in a dramatic loss in inhibitor potency. We attribute this effect to a negative steric interaction between the alkyl bridging units above (or below) the heterocyclic ring systems and an active-site amino acid residue. Conformational restriction of THIQ employing a bridging unit that is not located above (or below) the ring system results in only slightly diminished activity compared to THIQ itself. The relative activities of 4-8 were examined in terms of the conformational descriptors tau 1 and tau 2. Although there is no correlation between tau 1 and activity as a PNMT inhibitor, a qualitative relationship between tau 2 (endo or exo) and activity with PNMT is apparent. We believe that the binding of the N-H and/or N-lone pair of electrons may influence the spatial orientation of these molecules at the active site, resulting in positive binding interactions for compounds 4 and 8 and negative interactions for analogues 5-7. The results from the current investigation are compared to those obtained from a similar study involving conformationally defined amphetamines.

Benzylamines↗

PubMed1988

Synthesis and evaluation of 3-substituted analogues of 1,2,3,4-tetrahydroisoquinoline as inhibitors of phenylethanolamine N-methyltransferase.

1,2,3,4-Tetrahydroisoquinoline (THIQ) and aryl-substituted derivatives of THIQ are potent inhibitors of the enzyme that catalyzes the formation of epinephrine--phenylethanolamine N-methyltransferase (PNMT, E.C. 2.1.1.28). In previous studies, we found that substitution of the 3-position of THIQ with a methyl group resulted in enhanced activity as an inhibitor for 3-methyl-THIQ with respect to THIQ itself. To more fully delineate this region of the PNMT active site, we have synthesized and evaluated other 3-substituted THIQ analogues that vary in both steric and electronic character. Extension of the methyl side chain in 8 by a single methylene unit results in diminished potency for 3-ethyl-THIQ, suggesting that this zone of the active site is spatially compact; furthermore, the region of steric intolerance may be located principally on only "one side" of the 3-position of bound THIQs, since the carbonyl containing (bent) analogues 3-(methoxycarbonyl)-THIQ and 3-(aminocarbonyl)-THIQ are much less capable of forming a strong enzyme-inhibitor dissociable complex compared to straight-chain derivatives possessing a similar steric component. The good activity of 3-(hydroxymethyl)-THIQ as a PNMT inhibitor cannot be explained solely by steric tolerance for this side chain. We believe that an active-site amino acid residue capable of specific (i.e., hydrogen bond) interactions is located in close proximity to the 3-position of bound THIQs and that association of the OH functionality with this active-site residue results in the enhanced in vitro potency of this analogue (Ki = 2.4 microM) compared to that of THIQ (Ki = 10.3 microM). Incorporation of a hydroxymethyl substituent onto the 3-position of the potent PNMT inhibitor 7,8-dichloro-THIQ (SKF 64139, Ki = 0.24 microM) did not result in the same enhancement in inhibitor potency for 17 (Ki = 0.38 microM). This result suggests that simultaneous binding in an optimal orientation of the aromatic halogens, secondary amine, and side-chain hydroxyl functionalities to the PNMT active site is not allowed in this analogue.

Chemical Phenomena↗

PubMed1988

Homoallylic amines related to zimeldine. A comparative study on neuronal serotonin and norepinephrine reuptake based on conformational analysis.

A number of tertiary and secondary homoallylic amines, i.e. (Z)- and (E)-4-(4-bromophenyl)-4-(3-pyridyl)-3-buten-1-ylamines, were synthesized in diastereomerically pure forms. The compounds were evaluated as neuronal norepinephrine (NE) and serotonin (5-HT) uptake inhibitors under in vitro and ex vivo conditions and compared with the tricyclics amitriptyline and nortriptyline having homoallylic side chains and with the corresponding diastereomers in the zimeldine series having allylic side chains. The Z isomers of the new homoallylic derivatives (3Z, 4Z) were specific 5-HT uptake inhibitors in analogy with the corresponding allylic derivatives zimeldine (1Z) and norzimeldine (2Z). Likewise, the selectivity profile of the homoallylic (3E, 4E) and the allylic (1E, 2E) derivatives was comparable. In general, the homoallylic compounds were less potent inhibitors than their allylic counterparts. The similarities and discrepancies were evaluated in terms of conformational preferences determined by CAMSEQ molecular mechanics calculations. Homonorzimeldine (4Z) can accommodate energetically favored, but less populated, conformations having amino nitrogen atom to aromatic ring center distances comparable to those in norzimeldine. These facts correlate to retained 5-HT selectivity but diminished potency of 4Z compared to 2Z.

Animals↗

PubMed1988

Inhibition of norepinephrine transport into synaptic vesicles by amphetamine analogs.

The abilities of several amphetamine analogs with restricted conformations to inhibit uptake of [3H]norepinephrine into synaptic vesicles isolated from rat brain cerebral cortex were compared. [3H]Norepinephrine was accumulated in the vesicles with a Km of 3.5 microM and a Vmax of 7.6 pmol/g of tissue per min. This uptake was inhibited by reserpine (IC50, 6.4 nM), amphetamine (IC50, 2.5 microM) and eight amphetamine analogs. 2-Aminotetralin, the most flexible of the analogs (capable of assuming both gauche and anticonformations), was the most potent (IC50, 22 microM). The side chain of amphetamine was held in one of its two low energy conformations [transantiperiplanar (extended) and gauche (folded)]. This was accomplished by using the benzobicyclo[2.2.1]heptane, benzobicylco[2.2.2]octane, or tetrahydroisoquinoline ring systems. The potencies of all of the conformationally defined analogs were reduced with IC50 values of 120 to 370 microM and the potency differences between anti- and gauche conformations were small. These results are in contrast to those obtained by us earlier for inhibition of neuronal reuptake and suggest that vesicular uptake may be more conformationally restrictive than neuronal reuptake. It is possible that: 1) the amphetamine pharmacophore must retain some conformational flexibility for vesicular uptake (hence activity for 2-aminotetralin but not for the rigid analogs); 2) there is another higher energy conformation of amphetamine not present in any of the rigid analogs evaluated that is required for optimal interaction with the vesicular uptake site; or 3) the extra steric bulk of the bridging atoms in the conformational analogs severely interferes with binding at the vesicular uptake site.

Adenosine Triphosphate↗

PubMed1987

Binding orientation of amphetamine and norfenfluramine analogues in the benzonorbornene and benzobicyclo[3.2.1]octane ring systems at the active site of phenylethanolamine N-methyltransferase (PNMT)

In a continuation of studies directed at characterizing the conformational basis of binding beta-phenylethylamines at the active site of phenylethanolamine N-methyltransferase (PNMT), anti-10-amino- (12) and syn-10-amino-5,6,7,8-tetrahydro-5,8-methano-9H-benzocycloheptene (13) were prepared and evaluated as substrates and inhibitors for PNMT. These conformationally defined amphetamine analogues mimic a low energy half-chair form of 2-aminotetralin (2AT). Further, in order to determine the active site binding orientation of beta-phenylethylamines bearing aryl lipophilic substituents, the aryl trifluoromethyl-substituted derivatives of 12 and 13 (20-27), as well as anti-9-amino-5-(trifluoromethyl)-(18) and anti-9-amino-6-(trifluoromethyl) benzonorbornene (19), were prepared and evaluated. The competitive inhibition displayed by the fully extended analogue 12 coupled with the uncompetitive kinetics exhibited by the folded isomer 13 supports previous findings that a fully extended side chain conformation is optimal for binding to the active site of PNMT. In addition, the fact that 12 displayed enhanced affinity as an inhibitor over its beta-phenylethylamine counterparts in the benzonorbornene and 1,4-ethanonaphthalene ring systems suggests that a half-chair conformation is preferred when 2AT analogues interact at the active site of the enzyme. This would be consistent with previous results that PNMT preferentially binds molecules with a more coplanar relationship between the aromatic ring and the amino nitrogen. The lack of activity as a substrate in 12 indicates that the negative steric interactions of the ethano bridging unit prohibits it from binding in a manner consistent with the known PNMT substrates exo-2-amino- (6) and anti-9-aminobenzonorbornene (8). Given the emergence of activity as a substrate in 20 and 21 (the 1-trifluoromethyl- and the 2-trifluoromethyl-substituted derivatives of 12), it appears that the positive interaction of the trifluoromethyl group orients these analogues in a manner in which the ethano bridge lies in regions of steric bulk tolerance. This would suggest that the region of steric intolerance has a degree of directionality. Finally, although the aromatic ring binding region of the active site of PNMT contains a large degree of lipophilic character, only specific spatial orientations between the trifluoromethyl group and the amino nitrogen of aryl trifluoromethyl-substituted beta-phenylethylamines allow both to interact simultaneously in a manner that allows the amine to bind in a region of the active site in which methylation can occur.

Amphetamines↗

PubMed1987

Inhibition of phenylethanolamine N-methyltransferase (PNMT) by aromatic hydroxy-substituted 1,2,3,4,-tetrahydroisoquinolines: further studies on the hydrophilic pocket of the aromatic ring binding region of the active site.

In a continuation of studies directed toward characterizing the hydrophilic pocket within the aromatic ring binding region of the active site of phenylethanolamine N-methyltransferase (PNMT), 5-, 6-, 7-, and 8-hydroxy-1,2,3,4-tetrahydroisoquinoline were prepared and evaluated as substrates and inhibitors of PNMT. In order to discern the necessity of an acidic hydrogen for interaction at this pocket the corresponding methyl ethers were also evaluated. The enhanced affinity of 7-hydroxy-1,2,3,4-tetrahydroisoquinoline (16) versus tetrahydroisoquinoline (13) itself indicates that a hydrophilic pocket exists off of carbon C7 in bound tetrahydroisoquinolines. The diminished affinity of the corresponding methyl ether is consistent with a requirement for the acidic hydrogen of 16 for interaction of the aromatic hydroxyl at this site. From the relative activities of the other regioisomeric aromatic hydroxyl-substituted tetrahydroisoquinolines, their corresponding methyl ethers, and 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, it appears that the hydrophilic pocket is spatially compact with respect to bound tetrahydroisoquinolines and is surrounded by larger areas of lipophilic character. To allow a comparison of the results of this study with previous data on bound beta-phenylethylamines, the methyl ethers of 5-, 6-, 7-, and 8-hydroxy-exo-2-aminobenzonorbornene and of 5- and 6-hydroxy-anti-9-aminobenzonorbornene were also evaluated for their activity as substrates and inhibitors for PNMT. The results of this study are in agreement with previous findings for bound beta-phenylethylamines and support the conclusion that the natural substrate for PNMT, norepinephrine, has a different active site binding orientation than most known substrates and competitive inhibitors of the enzyme.

Binding Sites↗

PubMed1986

Binding requirements of phenolic phenylethylamines in the benzonorbornene skeleton at the active site of phenylethanolamine N-methyltransferase.

In order to determine the active site binding orientation of norepinephrine, a series of conformationally defined analogues of the tyramines, in which the ethylamine side chain is held fixed by incorporation into a benzonorbornene skeleton, were prepared and evaluated for phenylethanolamine N-methyltransferase (PNMT) activity. While exo-2-amino-5- and exo-2-amino-8-hydroxybenzonorbornene (7 and 10, respectively) were prepared from 5-methoxybenzonorbornadiene by azidomercuration/demercuration and reduction, it was necessary to employ both normal (inversion of configuration) and abnormal (retention of configuration) Mitsunobu reactions to prepare, stereoselectively, exo-2-amino-6- and exo-2-amino-7-hydroxybenzonorbornene (8 and 9, respectively) from 6- and 7-methoxybenzonorbornen-2-ol. None of the six analogues were substrates. However, exo-2-amino-6-hydroxybenzonorbornene (8) and anti-9-amino-6-hydroxybenzonorbornene (12) displayed significant activity as inhibitors toward PNMT. The greater potency of 8 and 12, as compared to the parent unsubstituted analogues exo-2-amino- and anti-9-amino-benzonorbornene (4 and 5, respectively), indicates the presence of a spatially compact hydrophilic pocket within the aromatic ring binding region of the active site of the enzyme. Furthermore, the greater activity of 12, relative to 8, is consistent with an active site binding preference for molecules in which a more coplanar relationship exists between the aromatic ring and the amine nitrogen. From the findings of this study, it appears that norepinephrine has a different active site binding orientation than most known substrates and competitive inhibitors of PNMT.

Binding Sites↗

PubMed1986

Conformational analysis of nisoxetine and fluoxetine, selective inhibitors of norepinephrine and serotonin reuptake: are conformational differences an explanation of neurotransmitter selectivity?

Low energy conformations and the pathways between them have been calculated for nisoxetine (N-methyl-3-phenyl-3-(o-methoxyphenoxy)-propylamine), (I), a selective inhibitor of neuronal reuptake of norepinephrine, and fluoxetine (N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine), (II), a selective inhibitor of neuronal reuptake of serotonin. Results are presented as a series of energy maps and ORTEP drawings. Conformational preferences of the protonated forms and preferred conformations in aqueous solution are also established. The CAMSEQ empirical potential method was used throughout. Both the nisoxetine and fluoxetine systems are shown to exhibit the known 'folded-extended' conformational preferences of the phenethylamines. It is suggested that the observed conformational variation between the two systems may play a role in the pharmacological differences between nisoxetine and fluoxetine.

Chemical Phenomena↗

PubMed1984

Gas chromatographic quantitation of underivatized amines in the determination of their octanol-0.1 M sodium hydroxide partition coefficients by the shake-flask method.

The use of gas chromatography (GC) for the determination of 0.1 M sodium hydroxide-octanol partition coefficients (log P) for a wide variety of ethylamines is demonstrated. The conventional shake-flask procedure (SFP) is utilized, with the addition of an internal reference, which is cleanly separated from the desired solute and solvents on a 10% Apiezon L, 2% potassium hydroxide on 80-100 mesh Chromosorb W AW column. The partitioned solute is extracted from the aqueous phase with chloroform and analyzed by GC. The method provides an accurate and highly reproducible means of determining log P values, as demonstrated by the low relative standard errors. The technique is both rapid and extremely versatile. The use of the internal standard method of analysis introduces consistency, since variables like the exact weight of solute are not necessary (unlike the traditional SFP) and the volume of sample injected is not critical. The technique is readily accessible to microgram quantities of solutes, making it ideal for a wide range of volatile, amine-bearing compounds.

Chromatography, Gas↗

PubMed1984

Synthesis and anticonvulsant activity of some substituted lactams and amides.

Thirteen derivatives of 3-phenyl-2-piperidinone were synthesized and evaluated for anticonvulsant activity. The most active compounds from this group included two simple lactams, 3-hydroxy-1-methyl-3-phenyl-2-piperidinone and 3-methoxy-3-phenyl-2-piperidinone, and two N-ethoxycarbonyl lactams, 1-(ethoxycarbonyl)-3-hydroxy-3-phenyl-2-piperidinone and 1-(ethoxycarbonyl)-3-methoxy-3-phenyl-2-piperidinone, whose anticonvulsant activity was comparable to or better than that for valproic acid. Four related acyclic amides were also prepared, but these were essentially inactive as anticonvulsants.

Amides↗

PubMed1984

Inhibitors of phenylethanolamine-N-methyltransferase: effects on brain catecholamine content and blood pressure in DOCA-salt hypertensive rats.

Inhibitors [2-cyclooctyl-2-hydroxyethylamine (CONH), 1 aminomethylcycloundecanol (CUNH), 7,8-dichloro-1,2,3,4-tetrahydroisoquinoline (SKF64139), 2,3-dichloro-alpha-methylbenzylamine (DCMB), 8,9-dichloro-2,3,4,5-tetrahydro-1H-2-benzazepine(LY134046)] of phenylethanolamine N-methyltransferase (PNMT) were found to reduce blood pressure in deoxycorticosterone-salt (DOCA-salt) hypertensive rats. CONH, CUNH and DCMB, but not SKF64139 and LY134046, also lowered blood pressure in normotensive control rats. All of the PNMT inhibitors tested lowered hypothalamic epinephrine (Epi) content in both DOCA-salt hypertensive and normotensive rats. DCMB, SKF64139 and LY134046 also lowered brainstem Epi in both animal groups. From these data a good correlation could not be made between the blood pressure lowering effects of PNMT inhibitors and their effects on hypothalamic Epi content as had been observed in other animal models of hypertension (e.g. spontaneously hypertensive rats).

Animals↗

PubMed1983

An extension of the f-fragment method for the calculation of hydrophobic constants (log P) of conformationally defined systems.

An extension of the popular fragment methods for the calculation of octanol--water partition coefficient (log P) values of conformationally defined compounds is presented. Correction factors for both trans-antiperiplanar and gauche conformational isomers have been developed for both the Rekker and Leo fragment methods and successfully applied to a large, diverse group of conformationally defined phenethylamines. This approach is easy to use and only requires one additional correction factor per isomer. This method thus allows, for the first time, conformation to be taken into account for the fragment calculation of log P values.

Chemical Phenomena↗

PubMed1982

Conformational preferences of dopamine analogues for inhibition of norepinephrine N-methyltransferase. Conformationally defined adrenergic agents.

A series of analogues of dopamine (DA) with varying degrees of conformational flexibility have been examined as potential substrates or competitive inhibitors of the enzyme norepinephrine N-methyltransferase (NMT). A conformationally defined (rigid) analogue of the fully extended conformation of DA, 2-amino-6,7-dihydroxybenzonorbornene hydrobromide (3; 6,7-D2HX) proved to be a better substrate than the non-catechol parent 2-aminobenzonorbornene (4; 2HX). However, analogues 3 and 4 displayed equivalent competitive inhibitory activity toward phenylethanolamine (PEA). Neither 6,7-ADTN (5), a DA analogue in the 2-aminotetralin (2AT) system, nor 6,7-DTHIQ (7), a DA analogue in the tetrahydroisoquinoline (THIQ) system, showed substrate activity; 6,7-ADTN was a poorer competitive inhibitor than the parent 2AT but 6,7-DTHIQ was a better competitive inhibitor than its parent, THIQ (8). A tricyclic conformationally defined analogue 9 of 6,7-ADTN was devoid of either substrate or inhibitory activity. From these results it may be concluded that a fully extended side chain conformation is required for NMT substrate activity, and the better substrate activity for 6,7-D2HX compared to 4 is consistent with a proper catechol orientation for interaction with the norepinephrine (NE) binding site of NMT.

Adrenal Glands↗