The effects of an inhibitor of phenylethanolamine N-methyltransferase upon stimulated adrenal catecholamine release and excretion in the rat

Pendleton, Robert G.; Weiner, G; Jenkins, Bernard; Gessner, George

doi:10.1007/bf00509268

Cited by 12 publications

(10 citation statements)

References 5 publications

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“…However, kidney E levels were essentially unchanged by these treatments and urine E levels were decreased much less than plasma E, so renal tissue appears to synthesize renal and urinary E after Mx. Pendleton et al (14) found that urinary E was not reduced after Mx in rats. In man, Von Euler et al (15) reported unchanged urinary E levels after bilateral adrenalectomy.…”

Section: Discussionmentioning

confidence: 96%

Rat renal epinephrine synthesis.

Kennedy¹,

Elayan²

1989

J. Clin. Invest.

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Rats that underwent adrenal demedullation had a 93% decrease in plasma epinephrine (E) levels, but did not decrease their renal E. Even further treatment with 6-hydroxydopamine and reserpine failed to lower renal E levels. Similarly, urine E levels failed to decrease after adrenal demedullation and renal denervation. There is a renal E-synthesizing enzyme that differs from adrenal phenylethanolamine-N-methyltransferase (PNMT) in that it is only weakly inhibited by SKF 29661 and can synthesize epinine from dopamine, while adrenal PNMT does so poorly. When an adrenalectomized rat received intravenous IH]methionine, its urine contained radioactivity that appeared to be [HIE, with small amounts of[3Hepinine. However, after [Hjmethionine was infused in the renal artery, the major product in urine appeared to be I3Hjepinine, with a small amount of 13H]E. Adrenal demedullation induced renal E synthesis, but denervation returned the rate of renal E synthesis to control values. The combination of adrenal demedullation, 6-hydroxydopamine, and reserpine treatments increased renal E-forming activity to 350% of control.We conclude that appreciable portions of renal and urinary E are synthesized in the kidney by an enzyme distinct from PNMT. The enzyme is induced by some treatments that lower E and NE levels.

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Section: Discussionmentioning

confidence: 96%

Rat renal epinephrine synthesis.

Kennedy¹,

Elayan²

1989

J. Clin. Invest.

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“…Carbon chemical shifts are reported in ppm relative to CDCl 3 (77.0 ppm). For the hydrochloride and hydrobromide salts of these THIQs, NMR spectra were recorded in either deuterated dimethyl sulfoxide (DMSO-d6) and the chemical shifts reported relative to DMSO (2.49 ppm for 1 H and 39.5 ppm for 13 C) or deteurated methanol (CD3OD) (3.31 ppm for 1 H and 49.2 ppm for 13 C). Coupling constants (J) are reported in hertz (Hz), and s, d, t, q, m, br, and ex refer to singlet, doublet, triplet, quartet, multiplet, broad, and exchangeable, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…12 SK&F 29661 (3) is a highly potent THIQ-type inhibitor of PNMT but displays very poor affinity for the R 2adrenoceptor (Table 1). Unfortunately, autoradiographic studies have shown that 3 is unable to penetrate the BBB, 13 presumably due to the high polarity of the sulfonamide, making it a poor candidate for physiological studies.…”

Section: Introductionmentioning

confidence: 99%

“…20 Therefore, a new enantiospecific synthesis for the production of both 3-hydroxymethyl-and 3-fluoromethyl-THIQs was proposed. Retrosynthetic analysis of Ror S-3-hydroxymethyl-THIQs (8, 9, 14) and 3-fluoromethyl-THIQs (11)(12)(13)15) indicates that both series of compounds could be derived from a common intermediate (16), which could be synthesized in enantiomerically pure form from either D-or L-phenylalanine (17) (Figure 2). This synthesis has several advantages over those previously used.…”

Section: Introductionmentioning

confidence: 99%

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Enantiospecific Synthesis of 3-Fluoromethyl-, 3-Hydroxymethyl-, and 3-Chloromethyl-1,2,3,4-tetrahydroisoquinolines as Selective Inhibitors of Phenylethanolamine N-Methyltransferase versus the α₂-Adrenoceptor

Grunewald

Caldwell

et al. 1999

J. Med. Chem.

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An enantiospecific method was developed for the synthesis of 3-fluoromethyl-, 3-hydroxymethyl-, and 3-chloromethyl-7-substituted-1,2,3,4-tetrahydroisoquinolines (THIQs) from phenylalanine. Biochemical evaluation of the enantiomers of these compounds at both PNMT and the alpha(2)-adrenoceptor indicates that both sites display similar stereoselectivity. Overall the R-enantiomer was usually the more potent enantiomer at both PNMT and the alpha(2)-adrenoceptor for these 3-fluoromethyl-, 3-hydroxymethyl-, and 3-chloromethyl-THIQs. The one exception is 3-hydroxymethyl-7-nitro-THIQ (9), which was found to display the opposite stereoselectivity at the alpha(2)-adrenoceptor. A comparison of the PNMT inhibitory potency of the enantiomers of these 3-fluoromethyl-, 3-hydroxymethyl-, and 3-chloromethyl-THIQs indicates that all of the 3-substituted-THIQs displayed similar inhibitory potency for PNMT. However, the nature of the 3-substituent was found to have a major effect on the alpha(2)-adrenoceptor affinity of these compounds with the 3-hydroxymethyl- and 3-fluoromethyl-THIQs having the highest affinity and THIQs containing the 3-chloromethyl moiety the least. Compounds R-3-fluoromethyl-7-cyano-THIQ (R-12) and R-3-fluoromethyl-7-N-(4-chlorophenyl)aminosulfonyl-THIQ (R-13) and both enantiomers of 3-chloromethyl-7-nitro-THIQ (R- and S-30) are the most selective inhibitors in this study and display selectivities (alpha(2)-adrenoceptor K(i)/PNMT K(i)) greater than 200. These compounds give important insight into the steric and stereochemical preferences of both PNMT and the alpha(2)-adrenoceptor, which should assist in the development of new PNMT inhibitors.

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“…17 In spite of this apparent "tolerance" to PNMT inhibition under basal conditions, chronic administration of DCTQ will inhibit the release of epinephrine in response to repeated injections of 2-deoxy-Dglucose. 22 This finding suggests that the compound may inhibit the synthesis and release of adrenal epinephrine in response to stress. Autoradiographic studies have shown that DCTQ gains access to the central nervous system (CNS).…”

mentioning

confidence: 99%

Studies with a PNMT inhibitor

Dubb

Stote

Alexander

et al. 1979

Clin Pharma and Therapeutics

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DCTQ (SK&F 64139) is a potent inhibitor of both adrenal and central nervous system (CNS) phenylethanolamine N-methyltransferase (PNMT). In animal studies, a plasma level of 0.35 microgram/ml was associated with 50% inhibition of both adrenal and central PNMT. We performed single-dose phase I studies with DCTQ in man. Plasma drug levels up to 6.26 microgram/ml were readily obtained. There were few subjective and no objective clinical changes. DCTQ did not alter blood pressure or cause CNS symptoms in man. Furthermore, resting plasma and urinary catecholamines did not change after DCTQ. The study suggests that acute inhibition of PNMT under resting conditions is without significant clinical effect.

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The effects of an inhibitor of phenylethanolamine N-methyltransferase upon stimulated adrenal catecholamine release and excretion in the rat

Cited by 12 publications

References 5 publications

Rat renal epinephrine synthesis.

Rat renal epinephrine synthesis.

Enantiospecific Synthesis of 3-Fluoromethyl-, 3-Hydroxymethyl-, and 3-Chloromethyl-1,2,3,4-tetrahydroisoquinolines as Selective Inhibitors of Phenylethanolamine N-Methyltransferase versus the α₂-Adrenoceptor

Studies with a PNMT inhibitor

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The effects of an inhibitor of phenylethanolamine N-methyltransferase upon stimulated adrenal catecholamine release and excretion in the rat

Cited by 12 publications

References 5 publications

Rat renal epinephrine synthesis.

Rat renal epinephrine synthesis.

Enantiospecific Synthesis of 3-Fluoromethyl-, 3-Hydroxymethyl-, and 3-Chloromethyl-1,2,3,4-tetrahydroisoquinolines as Selective Inhibitors of Phenylethanolamine N-Methyltransferase versus the α2-Adrenoceptor

Studies with a PNMT inhibitor

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Enantiospecific Synthesis of 3-Fluoromethyl-, 3-Hydroxymethyl-, and 3-Chloromethyl-1,2,3,4-tetrahydroisoquinolines as Selective Inhibitors of Phenylethanolamine N-Methyltransferase versus the α₂-Adrenoceptor