Cardiovascular Activity of SK&amp;F 64139 in the Hypertensive Rat

Jp, Hieble; Jp, McCafferty; Jm, Roesler; Rg, Pendleton; Gessner, George; Carey, Robert M.; Hm, Sarau; Goldstein, M

doi:10.1097/00005344-198309000-00029

Cited by 3 publications

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“…The hydrochloride salt was recrystallized from MeOH-Et2O as colorless needles: mp 222-223 °C dec; EIMS m/z 192 (M + 1, 6), 191 (M + , 33), 190 (M + -1, 100), 176 (15), 162 (46), 131 (73), 103 (48), 77 (50), 51 (35). Anal.…”

Section: Methodsmentioning

confidence: 99%

“…7-Acetamido-THIQ (26) was made in a straightforward manner from 42, which was synthesized as described previously. 21 The greater hydrolytic susceptibility of the aliphatic trifluoroacetamide as compared to the aromatic acetamide led to the formation of 26 on treatment of 43 with K 2 CO 3 in MeOH (Scheme 6).…”

Section: Chemistrymentioning

confidence: 99%

“…5 However, no acute blood pressure changes were noted with the peripherally active PNMT inhibitor SK&F 29661 (2, 7-aminosulfonyl-1,2,3,4-tetrahydroisoquinoline), 5 implying the role of only central epinephrine in regulating baroreceptor reflex activity. 5,6 This observation provided an impetus to develop a potent PNMT inhibitor which can be utilized as a novel antihypertensive agent. Unfortunately, most of the well-studied PNMT inhibitors, such as 1, exhibit strong affinity for the R 2 -adrenoceptor.…”

Section: Introductionmentioning

confidence: 99%

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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

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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.

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Section: Methodsmentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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

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“…It has been shown that CNS-active PNMT inhibitors such as SK&F 64139 (1, Figure 1) provide a decrease in brain epinephrine content and peripheral blood pressure when administered to hypertensive rats 12. By contrast, PNMT inhibitors such as SK&F 29661 (2, Figure 1) that do not cross the blood–brain barrier, are ineffective in lowering blood pressure 6.…”

mentioning

confidence: 99%

Time-dependent inactivation of human phenylethanolamine N-methyltransferase by 7-isothiocyanatotetrahydroisoquinoline

Caine

Thomson

et al. 2009

Bioorganic & Medicinal Chemistry Letters

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Halogenated and Metallated Isoquinolines and Their Hydrogenated Derivatives

Nair¹,

Premila²

1990

Chemistry of Heterocyclic Compounds: A Series of Monographs

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Cardiovascular Activity of SK&F 64139 in the Hypertensive Rat

Cited by 3 publications

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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

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

Time-dependent inactivation of human phenylethanolamine N-methyltransferase by 7-isothiocyanatotetrahydroisoquinoline

Halogenated and Metallated Isoquinolines and Their Hydrogenated Derivatives

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Cardiovascular Activity of SK&F 64139 in the Hypertensive Rat

Cited by 3 publications

References 0 publications

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

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

Time-dependent inactivation of human phenylethanolamine N-methyltransferase by 7-isothiocyanatotetrahydroisoquinoline

Halogenated and Metallated Isoquinolines and Their Hydrogenated Derivatives

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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

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