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The Role of the Merrifield Solid Phase Method in the Discovery and Exploration of a New Class of Selective Vasopressin Hypotensive Agonists

  • Bruce Merrifield Commemorative Issue
  • Published:
International Journal of Peptide Research and Therapeutics Aims and scope Submit manuscript

The Merrifield solid phase method (MSPM) has been of inestimable value in studies aimed at the design of selective agonists and antagonists of the V1a (vascular), V1b (pituitary), V2 (renal) and OT (uterine) receptors for vasopressin (VP) and oxytocin (OT). Here we describe how, 40 years after the landmark syntheses of oxytocin and vasopressin by Vincent du Vigneaud and colleagues, it led to the discovery of a new class of vasopressin agonists which exhibit selective hypotensive activity. We also point to the role of serendipity in this discovery. We furthermore show how the MSPM has been of inestimable value in facilitating a rapid and comprehensive structure activity study of the lead hypotensive peptide: d(CH2)5[D-Tyr(Et)2,Arg3,Val4]AVP (A) giving rise to d(CH2)5[D-Tyr(Pri)2,Arg3,Val4,Lys7,Eda9]LVP (B) which exhibits a 30-fold enhancement in vasodepressor potency relative to (A). Here, we also report a structure activity study of (B) with single modifications at position 3 (Lys, Nar) and 4 (Cha, Nle, Leu, Abu, Nva, Thr, Har) and combined modifications at positions 3 and 9 (Nar and EdaG) and 7 and 9 (Arg and Eda ← retro Tyr). All modifications of (B) are well tolerated with good retention of vasodepressor potency. These findings offer promising clues to the design of more potent VP hypotensive agonists and of critically needed antagonists of the putative VP vasodilating receptor. The Merrifield Solid Phase Method will continue to play a pivotal role in these studies.

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Abbreviations

 :

 

AVP:

arginine vasopressin

LVP:

lysine vasopressin

VP:

vasopressin

OT:

oxytocin, D-Tyr(Et), O-ethyl-D-tyrosine

D-Tyr(Pri):

O-i-propyl-D-tyrosine

Abu:

2-aminobutanoic acid

Aic:

2-aminoindane-2-carboxylic acid

Atc:

2-aminotetraline-2-carboxylic acid

Cha:

1-amino-cyclopentane-1-carboxylic acid (cyclohexylalanine)

Oic:

Octahydroindole-2-carboxylic acid

Tic:

1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

(OH)Tic:

1,2,3,4-tetrahydroisoquinoline-7-hydroxy-3-carboxylic acid

Har:

homoarginine, Nar, norarginine

Nva:

norvaline

Eda:

ethylenediamine

EdaG:

1-amino-2-guanidinoethane

d(CH2)5 :

β-mercapto-β,β-pentamethylenepropionyl

d(CH2)5(Mob):

β-(4-methoxybenzyl)mercapto-β,β-pentamethylenepropionyl

Eda←Tyr:

Eda retro-tyrosine

d(CH2)5[D-Tyr(Et)2]VAVP:

[1-(β-mercapto-β,β-pentamethylene propionic acid) -2-O-ethyl-D-tyrosine, 4-valine]arginine vasopressin

d(CH2)5[D-Tyr(Et)2,Arg3,Val4]AVP (A):

[1-(β-mercapto-β,β-pentamethylene propionic acid) -2-O-ethyl-D-tyrosine, 3-arginine, 4-valine]arginine vasopressin

DMF:

dimethylformamide

DCC:

dicyclohexylcarbodiimide

HOBt:

1-hydroxybenzotriazole, ONp, 4-nitrophenyl ester

Boc:

t-butyloxycarbonyl

Bzl:

benzyl

Tos:

tosyl

Z:

benzyloxycarbonyl

Mob:

4-methoxybenzyl

Z(2Cl):

2-chlorobenzyloxycarbonyl

AcOH:

acetic acid

TFA:

trifluoroacetic acid

DIPEA:

diisopropylethylamine

TLC:

thin layer chromatography

HPLC:

high performance liquid chromatography, ESMS, electro-spray mass spectrometry

AUC:

area under the vasodepressor response curve

ED:

effective dose

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Acknowledgments

We thank Ms. Ann Chlebowski for her expert help in the preparation of this manuscript. This work was supported by the National Institute of General Medical Sciences grant GM-25280. We will be forever indebted to Bruce Merrifield for his special gift of the solid phase method and for his friendship, advice and support over the past 40 years.

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Authors and Affiliations

  1. Department of Biochemistry and Cancer Biology, The University of Toledo, Mail Stop #1010, Health Science Campus, 3000 Arlington Avenue, Toledo, OH, 43614-2598, USA

    Maurice Manning, Stoytcho Stoev & Ling Ling Cheng

  2. Department of Pharmacology, Weill Medical College of Cornell University, New York, NY, 10021, USA

    Nga Wo, W. Y. Chan & Hazel H. Szeto

Authors
  1. Maurice Manning
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  2. Stoytcho Stoev
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  3. Ling Ling Cheng
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  4. Nga Wo
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  5. W. Y. Chan
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  6. Hazel H. Szeto
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Correspondence to Maurice Manning.

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Dedicated to the memory of Professor Bruce Merrifield.

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Manning, M., Stoev, S., Cheng, L.L. et al. The Role of the Merrifield Solid Phase Method in the Discovery and Exploration of a New Class of Selective Vasopressin Hypotensive Agonists. Int J Pept Res Ther 13, 7–17 (2007). https://doi.org/10.1007/s10989-007-9089-9

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