in several steps. After each step, substances with outlying pA2 -values were el minated. ...... 6.78. 7.13. ______-______ Phe-Gln-Asn-Cys -Pro -erg-GlyNHZ. 8.4.
Int. J . Peptide Proiein Res. 31, 1988, 520-536
Structural requirements of the oxytocin receptor in rat uterus Free-Wilson analysis in a series of competitive oxytocin inhibitors * VLADIMIR PLISKA’ and JOERG HEINIGER
Znsfitute of Animal Science, Swiss Federal Insriiufe of Technology, ETH Zurich, Zirrich, Switzerland
Received 5 October, accepted for publication 24 November 1987
Published and newly calculated pA2-values of 147 neurohypophyseal hormone analogues (7 positions varied) acting as inhibitors of oxytocin on isolated ]at uterus in vitro have been subjected to fractionation according to the method by Free and Wilson which was slightly modified for this purpose. The computation was citrried out in several steps. After each step, substances with outlying pA2-values were el minated. The reduced group containing 73-79% of the original substances disp1ayc:d a high degree of additivity of side chain contributions (SCC). This group seems to follow the “participation” rule as formulated by Free and Wilson. Analysis of the group of eliminated substances and of the resulting SCC-spectrum (level diagram) enabled us to draw some conclusions concerning the structural requirements of receptoi binding: i) The intact ring structure is necessary for the peptide-receptor interaction: linear peptides or pepiides with an extended ring are always outliers; ii) Carba analogues (substitution with CH2in the disulfide ring) display better affinitiesthan pepfides with an S-S ring; D-Arg’ substitution decreases the binding affinity; iii) Considerably better additivity is achieved when peptides are divided into subgroups with vasopr:ssin-like and oxytocin-like features; populations of receptors more specific for vasopr :sin and for oxytocin, respectively, can be assumed. Estimates of the “true” receptor-peptide dissociation constants can be obtained by summation of the corresponding SCC‘s in each investigated position. The value obtained for oxytocin is identical with thc.36, 1861-1866 26. Crankshaw. D.J.. Branda, LJ,., Matlib, M.A. & Daniel. E.E. (1978) European J . Biochem. 86, 481486 27. Fuchs, A.-R.. Fuchs, F.. Hussli?, P., Soloff, M.S. & Fernstrom, M.J. (1982) Scienc.. 215, 1396-1398 28. PliSka, V. (1988) J . Receptor E'es. 8, 245-259 29. PliSka. V. (1984) J. Receptor bes. 4, 371-383 30. PliSka, V., Heiniger, J.. Muller-Lhotsky, A,, Pliska, P. & Ekberg. B. (1986) J . Biol Chem. 261, 1698416989 31. Soloff. M.S. & Swartz, T.L. (1973) J . Bid. Chem. 248, 6471-7478 Address: Prof. Dr. V. Pliiku lnstitut fur Nutztienvissenschaften ETH Zurich CH-8092 Zurich Switzerland
APPENDIX PA,-values of oxytocin antagonists on rat uterus in vitro
Competitive antagonists of uterus response in vitro (rat) to oxytocin are listed alphabetically with regard to abbreviations of amino acids in individual positions; abbreviations are listed in Table 1 of the text. Uterotonic assays were carried out in Munsick solution ( 1 5) or in a similar organ medium. pA2-values in the absence of magnesium (left-hand column) or
532
in the presence of 0.5 mM h[g2+ (right-hand column) are indicated. Rehences to communications presenting I'harmacological data are given at the end of the table. Newly calculated values are marked by asterisks. The list contains pA,-vah.es for nonapeptides with oxytocin-like st:ucture and for their N"-extended analo :ues published before the end of 1986.
Oxytocin receptor Amino
acid
r e f
sequence
-
AcCys - T y r ( M e )
-1le-Gln-Asn-Cys
-Pro
-Leu-GlyNHZ
7.58
KROl
________________________________________---------BAR 1 7.26 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _7 ._0_3 _ _ - - - - - -KREl ---JON 1 6.73 7.29 SIMl 4.40 SIMl 5.50 SIMl 5.44 POL I 4.52 KRO I 7.33 MELZ 7.30 SMY 1 6.57 SMY 1 * 6.91 SMY I 7.13 SMY 1 6.74 SMY 1 5.99 KROl 7.22 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _6 ._9 _ 0 _ _ - - - - - -E-I -S-l_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _6.91 _ _ _ _6.61 - - - - - - SMY - - - -I CHFII* -Leu-GlyNHZ 6.23 Cys -1le -1le-Leu-Asn-Cys - P r o LEE2 - - - - - -.1eu - 1 l e - G l n - A s n - C y s - P r o -Leu-GlyNHZ 5.23 CHAl* - - -- -- - Leu -1le-Leu-Asn-Cys - P r o -Leu-GlyNHZ 6.60 RUDI - - - - - - -Phe -1le-Gln-Rsn-Cys - P r o -Leu-GlyNHZ 6.78 LEBZ --- - - - -phe -1le-Gln-Asn-Cys - P r o -Leu-GlyNHZ 6.00 CHAI + - - - - - Phe -1le-Leu-Asn-Cys - P r o -Leu-GlyNHZ 6.48 RUD I - - - - - - P h e ( 4 E t ) -1le-Gln-Asn-Cys - P r o -Leu-GlyNHZ 6.36 LEE2 - - - - - p h e ( 4 E t ) -1le-Gln-Asn-Cys - P r o -Leu-GlyNHZ 8.15 RUO 1 - - - - - - - Phe(4Me) -1le-Gln-Asn-Cys - P r o -Leu-GlyNHZ 7 . 2 3 LEE2 - - - - - - p h e ( F 5 ) -1le-Gln-Asn-Cys - P r o -Leu-GlyNHZ 6.27 LEE2 - --- - t r p -1le-Gln-Asn-Cys - P r o -Leu-GlyNHZ 6.87 SIMl - - - - -T y r -Phe-Gln-Asn-Pen - P r o -Lys-GlyNHZ 6.60 PLI I - - - - - - T y r ( 31) -1le-Gln-Asn-Cys - P r o -Leu-GlyNHZ 7 . 0 5 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _7.00 _ _ _ _ _ - - - -FLO - - -I- - PLII - - - - - - - Tyr(3Me) -1le-Gln-Asn-Cys - P r o -Leu-GlyNHZ 6.79 - - - - - - - tyr(3NOZ)-Ile-Gln-Asn-Cys - P r o -Leu-GlyNHZ 6.28 LEBZ - -- -T y r ( 6 u ) +he-Gln-Asn-Cys - P r o -Lys-GlyNHZ 6.63 MEL I - - - - - - - T y r ( E t ) -1le-Gln-Asn-Cys - P r o -Leu-GlyNHZ 6.78 RUO I _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _7 _ _ _ -- 1 .13 MEL Phe-Gln-Asn-Cys - P r o -erg-GlyNHZ 8.4 MEL 3 ------ t y r ( E t ) -Phe-Gln-Asn-Cys - P r o -Arg-GlyNHZ 8.7 MEL 3 - - - - - - - T y r ( E t ) +he-Gln-Asn-Cys - P r o -Lys-GlyNHZ 7.10 MEL I Orn-GlyNHZ 8.4 MEL3 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ - - Thr-Asn-Cys - P r o -Om-GlyNHZ 8.3 MEL 3 - - - - - - t y r ( E t ) +he-Thr-Asn-Cys - P r o -0rn-GlyNHZ 8.3 MEL3 - - - - - - T y r ( E t ) +he-Val-Rsn-Cys - P r o -0rn-GlyNHZ 7 . 6 MEL 3 - -- --- - t y r ( E t ) -Phe-Val-Asn-Cys - P r o -Om-GlyNHZ 8.2 MEL3 - - - - - - - l y r ( M e ) -1le-Gln-Asn-Cys - P r o -Leu-GlyNHZ .7.05 RUD I .................................................. 6.68 MEL 1 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Phe-Gln-fkn-Cys - P r o -Arg-GlyNHZ 7 . 4 4 RAN 1 .................................................. 6 . 3 4 JON1 Ope -Phe -1le-Asn-Asn-Cys - P r o -0rn-GlyNHZ 7.98 7 . 5 5 MAN2 SAW1 _ _ _ _ _ _ _ - - - - _ - _ _Gln-Asn-Cys _ _ _ _ _ - - P r o -Leu-GlyNHZ 7 . 7 8 7.01 MAN2 SAW1 _---------------___-____________________ Orn-GlyNHZ 7 . 2 0 7.21 HANZ Sf3WI . . . . . . . . . . . . . . . . . . . . . Thr-Rsn-Cys - P r o -Leu-GlyNHZ 7.43 7 . 5 8 MAN2 SAW1 - - - - - -. Tyr -1le-Gln-Asn-Cys - P r o -Leu-GlyNHZ 6.94 NES I _-__________---_________________________-~-------6.94 VAV 1 _______---__-___________________________---------7. I 4 5 . 6 3 MAN3 --_--______________-____________________ Orn-GlyNHZ 7.89 6.97 SAW 1 Thr-Asn-Cys - P r o -Leu-GlyNHZ 7.59 MAN3 .................................................. 7.46 6.23 MAN3 Phe-Gln-Asn-Cys -MeAla-Arg-GlyNHZ 7.81 7.09 GRZ I P r o -Rrg-GlyNHZ 6.93 EAN I ___________---____________________ Sar -Arg-GlyNHZ 7 . 0 8 6.08 GRZ I ..................... Val-Asn-Cys - P r o -arg-GlyNHZ 7 . 2 3 MAN1
__________-_---_-
Phe-Gln-Asn-Cys -1le-Gln-Asn-Cys _ _ _ _ _ _ _ - _ - - - -Phe-Gln-Asn-Cys --_- - - - - - - T y r ( M e ) -1le-Gln-Asn-Cys Ala -Tyr -1le-Gln-Asn-Ala RaCys - T y r ( M e ) - 1 l e - G l n - A s n - C y s Eta - T y r ( E t ) -1le-Gln-Asn-Cys CnCys +he -1le-Gln-Asn-Cys - - - - - - P h e ( 4 E t ) -1le-Gln-Asn-Cys - - - - - - - Phe(4Me) -1le-Gln-Asn-Cys - - - - - - - Tyr(Cm) -1le-Gln-Asn-Cys - - - - - - - T y r ( E t ) -1le-Gln-Asn-Cys - - - - - T y r ( M e ) -1le-Gln-Rsn-Cys AcPen - 1 y r
-
-
--
-Pro -Pro -Pro -Pro -Pro -Pro -Pro -Pro -Pro -Pro -Pro -Pro -Pro
-Arg-GlyNHZ -Leu-GlyNHZ -Lys-GlyNHZ -Leu-GlyNHZ -Leu-GlyNHZ -Leu-GlyNHZ -Leu-GlyNHZ -Leu-GlyNHZ -Leu-GlyNHZ -Leu-GlyNHZ -Leu-GlyNHZ -Leu-GlyNHZ -Leu-GlyNHZ
- -
- -
- -
_______-_________ -
_____________________ _________--____-_
_______________-__________________
533
V. PliSka and J. Heiniger A m i n o
acid
sequence
ref
-
1ee1 8.46 7.76 7.8 MAN2 I OW2 MAN2 'tAUI 7.70 7.9 10u2 7.64 7.79 MAN2 '*AW 1 7.64 7.79 _ _ _ - - - - _ _ _ _ _ _Phe-Gln-Rsn-Cys ___7.61 BAN1 - P r o -Rrg-GlyNHZ KROl GlyCys-Tyr(Me) - 1 l e - G l n - A s n - C y s - P r o -Leu-GlyNHZ 6.85 5MI 1 Hcy -Tyr - 1 l e - G l n - A s n - H c y - P r o -Leu-GlyNHZ 6.02 SMI 1 6.74 Mba -Tyr - 1 l e - G l n - A s n - H c y - P r o -Leu-GlyNHZ 1 UNZ Mep -Dbt - 1 l e - G l n - A s n - C y s - P r o -Leu-GlyNHZ 7 . 0 8 VAV 1 7.24 - - - -- - - T y r - 1 l e - G l n - R s n - C y s - P r o -Leu-GlyNHZ . - - - - - - -. - - 7.41 10u2 .- - - - - - - - - - - 7 . 5 5 6.82 10w2 6.91 BAN2 --Orn-G1 yNHZ 7.81 _ _ _ _ _ . _Leu-Asn-Cys ____ ___7 _ O Y_ Cl -Leu-GlyNHZ - P r_ o _ . 0 2_ _ _ _ _ _ _ _ _ _Thr-Asn-Cys _ _ _ _- P .r _ ____ o _ 7 . 7_ 2 _ 7 . 3_ 6 10w2 -Leu-GlyNHZ __---__ _ _ _ _ -_ _ _ _ . 6.84 OYC 1 Phe-Gln-Asn-Cys P r o_-Lys-GlyNHZ DYC 1 Leu-Asn-Cys - P r o - L y s - G l yNHZ 6.69 - - - - - - - T y r ( E t ) - 1 l e - G l n - R s n - C y s - P r o - O r n-G1 yNH2 8 . 5 0 7 . 8 3 BAN2 - - -- -- Tyr(Me) - 1 l e - G l n - A s n - C y s - P r o -0rn-GlyNHZ 8.91 7.86 BAN2 MgCys - T y r ( M e ) - 1 l e - G l n - A s n - C y s - P r o -Leu-GlyNHZ 7.27 KROZ 6.16 UAU 1 6.60 VAV I LUNl 7.05 7.91 LEBZ 8.06 LEBZ 6.50 MELZ 7.03 PLIZ 8.73 LEBZ 8.06 LEBZ PLIZ 6.95 8.0 me14 me14 8.5 me14 8.4 me14 7.9 LEBZ 4.56 LEBZ 5.49 me14 8.2 KRUl 7.41 MEL 1 6.27 MEL 1 6.53 MEL 1 6.59 LEBZ 7.45 NELZ 7.73 7.81 MELZ MELZ 8.42 me14 8.7 MELZ 8.29 me14 8.5 7.19 MEL 1 7.39 MELZ 8.43 MELZ 7.98 MELZ 8.9 me14 - 1 l e - T h r - A s n - C y s - P r o -0rn-GlyNHZ 8.3 me14 7.8 - 1 l e - V a l - A s n - C y s - G l y -Arg-GlyNHZ me14 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _P r o -Rrg-GlyNHZ 8.45 MELZ - 1 l e - V a l - A m - C y s - P r o -arg-GlyNHZ 8.6 me14 - 1 l e - V a l - A s n - C y s - P r o -0rn-GlyNHZ 7.6 me14 - 1 l e - V a l - A s n - C y s - P r o -0rn-GlyNHZ 8.2 me14 5.65 -Phe-Gln-Asn-Cys - P r o -arg-GlyNHZ MELZ --Lys-GlyNHZ 7.18 MEL 1 8.9 - 1 l e - G l n - R s n - C y s - P r o -0rn-GlyNHZ me14
.....................
534
Oxytocin receptor t)
Flmxno
acid
sequence
PAZ
r e f
-
8.59 WILl 7.43 NES 1 7.53 LOW2 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ - -7.61 - - - - - - -7-. 1 5 LOW2 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ~ - - - - - - -Orn-GlyNHZ - - - - - - - - - - -7.69 7.21 BAN2 7.91 7 . 8 1 LOW2 _ _ _ _ _ _ _ _ _ _ _ _ _ _Thr-Asii-Cys ------- P r o -Leu-GlyNHZ GRZl _ _ _ _ _ _ _ _ _ _ _ _ _ _ - _ _ Phe-Gln-Asn-Cys -MeAla-Arg-GlyNHZ 7 . 5 4 6 . 8 ____________ ____ __ -------.----P r_ o _ -Rrg-GlyNHZ 8.15 7.19 KRUl 6.95 6 . 1 4 GRZl _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ - _ _ _ _ - - - Sar - - - - --Rrg-GlyNHZ -----Val-Asn-Cys - P r o -arg-GlyNHZ 6.62 LOW 1 8.25 7 . 5 5 BAN: - - - - - - - T y r ( E t ) -1le-Gln-Asn-Cys - P r o -0rn-GlyNHZ _ _ _ _ _ _ _ _ _ _ _ _ _ _T-h-r---A-s-r r-C y s - P r o -0rn-GlyNHZ 8.41 7 . 9 9 MAN4 - - - - - - T y r ( M e ) -1le-Gln-Asn-Cys - P r o -0rn-GlyNHZ 8.52 7 . 8 8 BAN2 _ _ _ _ _ _ _ _ _ _ _ _ _ _ - _ - Phe-Gln-Hsn-Cys - P r o -erg-GlyNHZ 8.13 7.24 KRUl KROl 7.82 MsCys - T y r ( M e ) -1le-(iln-fisn-Cys -Pro -Leu-GlyNHZ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 7.22 _ _ _ - - - - - - - - -BAR - 1 HRU I Pen -Leu - 1 l e - G l n - A s n - C y s - P r o -Leu-GlyNHZ 7 . 1 4 - - - - - - - Phe - 1 l e - T h r - A s n - C y s -Dhp -0rn-GlyNHZ 7.45 ORM I P r o -Leu-GlyNHZ 7.67 HRUZ - - - - - - - P h e ( 4 E t ) - 1 l e - G l n - A s n - C y s - P r o -Leu-GlyNHZ 7.78 LEBZ - - - - - - - p h e ( 4 E t ) -1le-Gln-Asn-Cys - P r o -Leu-GlyNH2 8.09 LEBZ -------Tyr - I l e - G 1 n- Asn-Cys -Dhp -Leu-Gl yNH2 7.10 ORM I _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ - - _ _ _ _ _ _ _ _ _ _ _ _ _ _P_r _o _ -Leu-GlyNHZ 6.86 VAV 1 6. 32 vflv 1 pen -Tyr - 1 l e - G l n - A s n - C y s - P r o -Leu-GlyNHZ FERI Pen -Tyr - I 1e-Le;- Asii-Cys - P r o -Leu-G1 yNH2 6.77 _ _ _ _ _ _ _ - _ _ _ _ _ _ Thr-Asn-Cys _----__ - P r o -Leu-GlyNHZ 7.55 HRUZ -- - - - - - - - ..- - - Phe-Gln-Asn-Cys - P r o -Lys-GlyNHZ 6.60 SIMl _________-_ -----_ - - - - - -SIMl -.6.86 Pen_ - P_ ro _ -Lys-GlyNHP SIMl - - - - - - - Tyr(t4e) - 1 l e - G l n - A s n - C y s - P r o -Leu-GlyNHZ 8 . 0 0 8. I 3 SIMl _ - _ _ _ _ _ - - - - - _Pie-Gln-Asn-Cys _--- P r o -Lys-GlyNHZ 7.26 KROl PvCys - T y r ( M e ) -1le-Gln-Asn-Cys - P r o -Leu-GlyNHZ 6.52 KRO I SarCys-Tyr(Me) -11;-Gln-Asn-Cys - P r o -Leu-GlyNHZ 4.49 POL 1 Ser -Tyr - 1 l e - G l n - A s n - S e r - P r o -Leu-GlyNHZ 6.14 LEBZ TgCys - p h e ( l E t ) -1le-Gln-Asn-Cys - P r o -Leu-GlyNHZ
MPP
-trp
- - --- --Tyr
-Phe-Ile-Asn-Cys -Pro - Ile--Gln-Asn-Cys -Pro
-Arg-GlyNHZ -Leu-GlyNHZ
_______________-_____
_ _ _ _ _ _ _ ^ _ _ _ _ _ _ _ _ _ _ _ _ - - - - - - - - - - - - - -
t ) 1 s t column: a ) No p A
2
M g - f r e e medium, 2nd column: 0.5 mM Mg.
-value i n d i c a t e d ; a u t h o r ’ s d a t a used f o r an e s t i m a t e .
REFERENCES BAN I
BAN2
BAR I
BIS 1
CHA 1 DYCl
FERI FLOl
Bankowski, K., Manning, M., Haldar, J. & Sawyer, W.H. (1978) J. Med. Chem. 21, 850853 Bankowski, K., Manning, M., Seto, J., Haldar, J. & Sawyer, W.H. (1980) Int. J . Peptide Protein Res. 16, 382-391 Barth, T., Krojidlo, M. & JoSt, K. (1976) in Peptides 1976 (Loffet, A,, ed.), pp. 491-498, Editions de I’Universite de Bruxelles, Brussels Bisset, G.W., Clark, B.J., Krejti, I., PolaEek, I. & Rudinger, J. (1970) Brit. J. Pharmacol. 40, 342-360 Chan, W.Y., Hruby, V.J. & d u Vigneaud, V. (1974) J . Pharm. Exp. Ther. 190, 77-87 Dyckes, D.F., Nestor, J.J. Jr., Ferger, M.F., du Vigneaud, V. & Chan, W.Y. (1974) 1. Med. Chem. 17, 969-972 Ferger, M.F. & Chan, W.Y. (1975) J . Med. Chem. 18, 1020-1022 Flouret, G., Terada, S., Nakahara, T., Nakagawa, S.H. & Hechter, 0. (1975) in Peptides:
GRZ I
HRU I HRU2
JON 1 KREl KROl
KR02
KRU 1
Chemistry, Structure and Biology (Walter, R . & Meienhofer, J., eds.), pp. 751-754, Ann Arbor Science Publ., Ann Arbor, MI Grzonka, Z., Kasprzykowski, F., Lammek, B., Gazis, D. & Schwartz, I.L. (1983) in Peptides 1982 (Blaha, K. & Maloii, P., eds.), pp. 445448, W. de Gruyter, Berlin Hruby, V.J., Deb, K.K. & Yamamoto, D.M. (1979) J . Med. Chem. 22, 7-12 Hruby, V.J., Mosberg, H.I., Hadley, M.E., Chan, W.Y. & Powell, A.M. (1980) Ini. J . Peptide Protein Res. 16, 372-381 Jones, D.A. & Sawyer, W.H. (1980) J . Med. Chem. 23, 696-698 Krejti, I., Kupkova, B., Barth, T. & JoSt, K . (1973) Physiol. Bohemoslov. 22, 31 5-322 Krojidlo, M., Barth, T., Servitova, L., Dobrovsky, K., JoSt, K. & Sorm, F. (1975) CON.Czech. Chem. Commun. 40,2708-2717 Krojidlo, M., Barth, T., Blaha, K. & JoSt, K. (1976) Coll. Czech. Chem. Commun. 41, 19541958 Kruszynski, M., Lammek, B., Manning, M.,
535
V. PliSka and J. Heiniger
LEBl
LEB2
LOW1
LOW2
LUN 1 LUN2 MAN I
MAN2
MAN3
MAN4
MELl
MEL2 MEL3
536
Seto. J.. Haldar, J. & Sawyer, W.H. (1980) J . Med. Chem. 23. 364-368 Lebl, M. & Barth. T. (1983) in Peptides Structure and Funcrion (Hruby. V.J. & Rich, D.H.. eds.), pp. 357-360, Pierce Chemical Corp., Rockford, IL Lkbl, M., Barth, T., Servitova, L. & JoSt, K. (1983) in Peptides 1982 (Blaha, K. & M a l o k P., eds.), pp. 457-460, W. de Gruyter. Berlin Lowbridge, J., Manning, M., Haldar, J. & Sawyer, W.H. (1978) J . Med. Chem. 21, 313315 Lowbridge, J., Manning, M.. Seto. J.. Haldar, J. & Sawyer, W.H. (1979) J . Med. Chem. 22. 565-569 Lundeil, E.O. & Ferger. M.F. (1975) J . Med. Chem. 18, 1045-1047 Lundell, E.O., Smith, C.W. & Ferger, M.F. (1975) J . Med. Chem. 18, 1262-1264 Manning, M., Lowbridge, J., Stier, C.T. Jr., Haldar, J. & Sawyer, W.H. (1977) J . Med. Chem. 20. 1228-1230 Manning. M.. Bankowski. K., Lowbridge. J., Turan, A.. Haldar, J., Seto, J. & Sawyer, W.H. (1979) in Peptides 1978 (Siemion. I.Z. & Kupryszewski, G., eds.). pp. 469474. Wroclaw University Press, Wroclaw Manning, M., Lowbridge, J., Seto, J., Haldar, J. & Sawyer, W.H. (1978) J . Med. Chem. 21, 179-182 Manning, M., Bankowski, K., Kruszynski, M., Seto, J., Haldar, J. & Sawyer, W.H. in Peptides 1981 (Brunfeldt, K., ed.), pp. 534-540, Scriptor, Copenhagen Melin, P., Vilhardt, H., Lindeberg, G., Larsson, L.E. & Akelund, M. (1981) J . Endocrinol. 88, 173-180 Melin, P. (1982) private communication Melin, P., Trojnar. J., Vilhardt, H . & Akelund,
MEL4
NESl ORM I
PLI 1 PLI2 POL1
RUDl SAW1
SIM 1
SMI 1 SMY I VAV I
WILl
M. (1983) in Pepridcs - St-ucture and Function (Hruby, V.J. & Rich, D.H , eds.), pp. 361-364, Pierce Chemical Co., Rocl:ford, IL Melin, P., Trojnar, J., Joh; nsson, B., Vilhardt, H. & Akelund, M (1986) J . Endocrinol. 111, 125-131 Nestor, J.J. Jr., Ferger, M.F. & du Vigneaud, V. (1975) J . Med. Chem. 18, 284-287 Ormberg, J.F., Rockway, T.W., Hruby, V.J., Hlavacek, J. & Chan, W.Y. (1983) in Eighth American Peptide Symposium, Tucson, AR, Abstract No. 10-8 PliSka, V., Marbach. P., V:iSak, J. & Rudinger, J. (1977) Experientia 33, 357-369 PliSka, V. & Marbach, P. (1978) European J . Pharmacol. 49, 2 13-222 PolaEek, I., KrejEi. I., Nes iadba, H. & Rudinger, J. (1970) European J . Pharmacol. 9, 239245 Rudinger, J., PliSka. V. & !CrejEi, 1. (1972) Rec. Progr. Hormone Rcs. 28, 31-166 Sawyer, W.H., Haldar, J.. Gazis, D., Seto, J., Bankowski, K . , Lowbrid,;e, J. Turan, A. & Manning, M. (1980) Endo Trinology 106, 81-91 Simek, P., Barth. T., Brtnil., F., Slaninova, J. & JoSt, K. (1983) in Pepfide: 1982 (Blaha, K. & Malon P., eds.), pp. 461-164, W. de Gruyter, Berlin Smith, C.W. & Ferger. h1.F. (1976) J . Med. Chem. 19, 250-254 Smyth, D. (1970) Biochins. Biphys. Acfn 200, 395-403 Vavrek, R.J., Ferger, M.. Allen, G.A., Rich, D.H.. Blomquist, A.T. I r du Vigneaud, V. (1972) J . Med. Cham. 15, 123-126 Wilson, L. Jr. & Flouret. (;. (1986) Nineteenth Annual Meeting of the SOI iety for the Study of Reproduction, Cornell University, Ithaca, NY. Abstract No. 195
