Inhibition of phenylethanolamine N-methyl transferase by benzylamines. 1. Structure-activity relations

Fuller, Ray W.; Molloy, Bryan B.; Day, W. A.; Roush, Betty W.; Marsh, Max M.

doi:10.1021/jm00260a003

Cited by 34 publications

(28 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Then the scientific interest was directed towards benzylamines and, also in this case, inhibitory potency has been improved by alogen substituents together with the addition of an α-methyl group [131]: ligand 54 was one of the first compounds to be used as an inhibitor of catecholamine biosynthesis in vivo.…”

Section: Cyclized Phenethylaminesmentioning

confidence: 99%

Agonists and Antagonists Targeting the Different α2-Adrenoceptor Subtypes

Gentili

Pigini²,

Piergentili³

et al. 2007

CTMC

View full text Add to dashboard Cite

Chemical and biological strategies have provided evidence for alpha(2)-receptor heterogeneity, to date classified in three different subtypes, alpha(2A), alpha(2B), and alpha(2C). These are widely distributed throughout the body and mediate numerous effects; therefore, the potential therapeutic indications of agonists and antagonists are numerous. Nevertheless, the lack of subtype-selectivity of the well-known compounds represents a major limit for their use. SAR studies may help to design new and more selective drugs.

show abstract

Section: Cyclized Phenethylaminesmentioning

confidence: 99%

Agonists and Antagonists Targeting the Different α2-Adrenoceptor Subtypes

Gentili

Pigini²,

Piergentili³

et al. 2007

CTMC

View full text Add to dashboard Cite

show abstract

“…55 The inverse relationship observed between the biochemical activity and the pK a of a series of benzylamines led to the hypothesis that the non-protonated form of benzylamine might be the active inhibitor species at PNMT. 55 However, there were two obvious problems with this hypothesis. First, the strong correlation between the σ value of the aromatic substituent and the pK a of the benzylamines suggested that the electron-withdrawing substituents may facilitate the binding of benzylamines to PNMT not by lowering the pK a , but by promoting an interaction between an electron deficient aromatic ring and the PNMT active site.…”

Section: Pnmtmentioning

confidence: 99%

“…Secondly, even in the most thorough study of substituted benzylamines, the pK a range was narrow and under the assay conditions (pH = 8.0) all of the compounds studied existed primarily as the protonated species. 55 This study of 3-mono-, di-and trifluoromethyl-THIQs compares compounds having a broad range of pK a values significantly above and below the pH of the assay, and is thus superior for determining the ionization state in which these compounds bind. Compounds that are either protonated under the assay conditions, such as 3-methyl-THIQs 11d and 15d (Table 4), or are primarily neutral under the assay conditions, such as 3-difluoromethyl-THIQs 11b and 15b are highly potent inhibitors, indicating that THIQ inhibitors can bind to PNMT as either the protonated or neutral species.…”

Section: Pnmtmentioning

confidence: 99%

Application of the Goldilocks Effect to the Design of Potent and Selective Inhibitors of Phenylethanolamine N-Methyltransferase: Balancing pK_a and Steric Effects in the Optimization of 3-Methyl-1,2,3,4-tetrahydroisoquinoline Inhibitors by β-Fluorination

et al. 2006

View full text Add to dashboard Cite

Abstract3-Methyl-1,2,3,4-tetrahydroisoquinolines (3-methyl-THIQs) are potent inhibitors of phenylethanolamine N-methyltransferase (PNMT), but are not selective due to significant affinity for the α 2 -adrenoceptor. Fluorination of the methyl group lowers the pK a of the THIQ amine from 9.53 (CH 3 ) to 7.88 (CH 2 F), 6.42 (CHF 2 ), and 4.88 (CF 3 ). This decrease in pK a results in a reduction in affinity for the α 2 -adrenoceptor. However, increased fluorination also results in a reduction in PNMT inhibitory potency, apparently due to steric and electrostatic factors. Biochemical evaluation of a series of 3-fluoromethyl-THIQs and 3-trifluoromethyl-THIQs showed that the former were highly potent inhibitors of PNMT, but were often non-selective due to significant affinity for the α 2 -adrenoceptor, while the latter were devoid of α 2 -adrenoceptor affinity, but also lost potency at PNMT. 3-Difluoromethyl-7-substituted-THIQs have the proper balance of both steric and pK a properties and thus have enhanced selectivity versus the corresponding 3-fluoromethyl-7-substituted-THIQs and enhanced PNMT inhibitory potency versus the corresponding 3-trifluoromethyl-7-substituted-THIQs. Using the "Goldilocks Effect" analogy, the 3-fluoromethylTHIQs are too potent (too hot) at the α 2 -adrenoceptor and the 3-trifluoromethyl-THIQs are not potent enough (too cold) at PNMT, but the 3-difluoromethyl-THIQs are just right. They are both potent inhibitors of PNMT and highly selective due to low affinity for the α 2 -adrenoceptor. This seems to be the first successful use of the β-fluorination of aliphatic amines to impart selectivity to a pharmacological agent while maintaining potency at the site of interest.

show abstract

“…In this quantitative structure−activity relationship (QSAR) study, only a narrow range of lipophilic substituents, such as chloro, bromo, iodo, fluoro, trifluoromethyl, and methyl, were used. The effect of the aromatic substituent on the p I 50 indicated that lowering the p K a increased the potency of benzylamines, and it was proposed that benzylamines bind to the active site of PNMT in the nonprotonated form . Using quantum chemical indices derived from semiempirical molecular orbital calculations, Otto et al examined the same data set of benzylamines studied earlier by Fuller.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Biochemical Evaluation, and Classical and Three-Dimensional Quantitative Structure−Activity Relationship Studies of 7-Substituted-1,2,3,4-tetrahydroisoquinolines and Their Relative Affinities toward Phenylethanolamine N-Methyltransferase and the α₂-Adrenoceptor^,1

et al. 1998

View full text Add to dashboard Cite

7-Substituted-1,2,3,4-tetrahydroisoquinolines (7-substituted-THIQs) are potent inhibitors of phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28), the enzyme involved in the biosynthesis of epinephrine. Unfortunately, most of these compounds also exhibit strong affinity for the alpha2-adrenoceptor. To design a selective (PNMT vs alpha2-adrenoceptor affinity) inhibitor of PNMT, the steric and electrostatic factors responsible for PNMT inhibitory activity and alpha2-adrenoceptor affinity were investigated by evaluating a number of 7-substituted-THIQs. A classical quantitative structure-activity relationship (QSAR) study resulted in a three-parameter equation for PNMT (PNMT pKi = 0.599pi - 0.0725MR + 1. 55sigmam + 5.80; n = 27, r = 0.885, s = 0.573) and a three-parameter equation for the alpha2-adrenoceptor (alpha2 pKi = 0.599pi - 0. 0542MR - 0.951sigmam + 6.45; n = 27, r = 0.917, s = 0.397). These equations indicated that steric effects and lipophilicity play a similar role at either active site but that electronic effects play opposite roles at either active site. Two binding orientations for the THIQs were postulated such that lipophilic and hydrophilic 7-substituents would not occupy the same region of space at either binding site. Using these two binding orientations, based on the lipophilicity of the 7-substituent, comparative molecular field analysis (CoMFA) models were developed that showed that the steric and electrostatic interactions at both sites were similar to those previously elaborated in the QSAR analyses. Both the QSAR and the CoMFA analyses showed that the steric interactions are similar at the PNMT active site and at the alpha2-adrenoceptor and that the electrostatic interactions were different at the two sites. This difference in electrostatic interactions might be responsible for the selectivity of THIQs bearing a nonlipophilic electron-withdrawing group at the 7-position. These QSAR and CoMFA results will be useful in the design of potent and selective (PNMT vs alpha2-adrenoceptor affinity) inhibitors of PNMT.

show abstract

Inhibition of phenylethanolamine N-methyl transferase by benzylamines. 1. Structure-activity relations

Cited by 34 publications

References 5 publications

Agonists and Antagonists Targeting the Different α2-Adrenoceptor Subtypes

Agonists and Antagonists Targeting the Different α2-Adrenoceptor Subtypes

Application of the Goldilocks Effect to the Design of Potent and Selective Inhibitors of Phenylethanolamine N-Methyltransferase: Balancing pK_a and Steric Effects in the Optimization of 3-Methyl-1,2,3,4-tetrahydroisoquinoline Inhibitors by β-Fluorination

Synthesis, Biochemical Evaluation, and Classical and Three-Dimensional Quantitative Structure−Activity Relationship Studies of 7-Substituted-1,2,3,4-tetrahydroisoquinolines and Their Relative Affinities toward Phenylethanolamine N-Methyltransferase and the α₂-Adrenoceptor^,1

Contact Info

Product

Resources

About

Inhibition of phenylethanolamine N-methyl transferase by benzylamines. 1. Structure-activity relations

Cited by 34 publications

References 5 publications

Agonists and Antagonists Targeting the Different &#945;2-Adrenoceptor Subtypes

Agonists and Antagonists Targeting the Different &#945;2-Adrenoceptor Subtypes

Application of the Goldilocks Effect to the Design of Potent and Selective Inhibitors of Phenylethanolamine N-Methyltransferase: Balancing pKa and Steric Effects in the Optimization of 3-Methyl-1,2,3,4-tetrahydroisoquinoline Inhibitors by β-Fluorination

Synthesis, Biochemical Evaluation, and Classical and Three-Dimensional Quantitative Structure−Activity Relationship Studies of 7-Substituted-1,2,3,4-tetrahydroisoquinolines and Their Relative Affinities toward Phenylethanolamine N-Methyltransferase and the α2-Adrenoceptor,1

Contact Info

Product

Resources

About

Agonists and Antagonists Targeting the Different α2-Adrenoceptor Subtypes

Agonists and Antagonists Targeting the Different α2-Adrenoceptor Subtypes

Application of the Goldilocks Effect to the Design of Potent and Selective Inhibitors of Phenylethanolamine N-Methyltransferase: Balancing pK_a and Steric Effects in the Optimization of 3-Methyl-1,2,3,4-tetrahydroisoquinoline Inhibitors by β-Fluorination

Synthesis, Biochemical Evaluation, and Classical and Three-Dimensional Quantitative Structure−Activity Relationship Studies of 7-Substituted-1,2,3,4-tetrahydroisoquinolines and Their Relative Affinities toward Phenylethanolamine N-Methyltransferase and the α₂-Adrenoceptor^,1