Comparative structural requirements of thirty GRF analogs for interaction with GRF- and VIP receptors and coupling to adenylate cyclase in rat adenopituitary, liver and pancreas

Robberecht, Patrick; Waelbroeck, Magalì; Coy, David H.; Neef, Philippe De; Camus, Jean Claude; Christophe, Jean

doi:10.1016/0196-9781(86)90164-6

Cited by 22 publications

(14 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PACAP(2-27) was already 50-fold less potent than PACAP(1-27) for binding but retained 90% of its intrinsic effect on adenylate cyclase. In line with other members of this family of peptides (including VIP, secretin and glucagon) [17,18,[23][24][25][26][27][28][29][30][31][32][33], it appears that, upon receptor recognition, the first two residues of PACAP(1-27) played an important role in adenylate cyclase activation, but the N-terminal His1 was not absolutely required. After further deletion, the of PACAP(3 -27), PACAP(5 -27), PACAP(6 -27), PACAP(7 -27) and PACAP(9 -27) were, respectively, 1 500-, 500-, 200-, 1500-and 3800-fold higher than that of PACAP(1-27), and these five PACAP fragments, having lost the ability to stimulate adenylate cyclase, behaved as antagonists (Table 2), i.e.…”

Section: Fig4 Correlation Between Ics0 (A) and K (Or Ki) (B) Of mentioning

confidence: 91%

Structural requirements for the occupancy of pituitary adenylate‐cyclase‐activating‐peptide (PACAP) receptors and adenylate cyclase activation in human neuroblastoma NB‐OK‐1 cell membranes

Robberecht

Gourlet

Neef

et al. 1992

European Journal of Biochemistry

Self Cite

205

107

View full text Add to dashboard Cite

In these structure activity studies, the 46 analogs of the 27‐amino‐acid form of the pituitary‐adenylate‐cyclase‐activating peptide, PACAP(1–27), and the 38‐amino‐acid form, PACAP(1–38), were either monosubstituted or bisubstituted at positions 1–3, 20 and 21 or N‐terminally shortened. All analogs were compared on human neuroblastoma NB‐OK‐1 cell membranes for their ability to occupy 125I‐[AcHis1]PACAP(1–27)‐labelled receptors (AcHis, Nα‐acetylhistidine) and to activate adenylate cyclase (in terms of potency and intrinsic activity). The monophasic slope of dose/effect curves on both parameters suggested interaction with one class of PACAP receptor. Residues 28–38 in the C‐terminally extended peptide, PACAP(1–38), played a favorable role in recognition, in that receptors coupled to adenylate cyclase were, in general, more sensitive to PACAP(1–38) analogs than to the corresponding PACAP(1–27) analogs. At variance with PACAP(6–27), PACAP(6–38) was well recognized and acted as a potent competitive antagonist (Ki 1.5 nM). Residues 1–3 were all important in enzyme activation: modification of the β‐turn potential gave full agonists (the LAla2 and DAla2 derivatives) or partial agonists (LPhe2 and DPhe2; LArg2 and DArg2; Glu3 and Asn3). Finally, a proper α‐helix was also important: the combined substitution of Lys21/Lys22 by Gly21/Gly22 decreased the binding affinity sharply.

show abstract

Section: Fig4 Correlation Between Ics0 (A) and K (Or Ki) (B) Of mentioning

confidence: 91%

Structural requirements for the occupancy of pituitary adenylate‐cyclase‐activating‐peptide (PACAP) receptors and adenylate cyclase activation in human neuroblastoma NB‐OK‐1 cell membranes

Robberecht

Gourlet

Neef

et al. 1992

European Journal of Biochemistry

Self Cite

205

107

View full text Add to dashboard Cite

show abstract

“…Analogs JV-1-50, JV-1-51, JV-1-52, and JV-1-53 (Table 1) were intended to be VIP antagonists and contained the D-Phe 2 substituent instead of D-Arg 2 , because this substitution was reported to produce predominantly VIP antagonistic property on incorporation into GHRH analogs (8,10). The structures of VIP antagonists JV-1-50 and JV-1-51 are closely related to those of GHRH antagonist JV-1-36 and JV-1-42, the only differences between these four compounds being in the first two amino acids and the N-acyl moiety.…”

Section: Discussionmentioning

confidence: 99%

“…Antagonistic analogs of GHRH JV-1-36, JV-1-38, and JV-1-42 (Table 1) were previously synthesized in our laboratory as part of our program to develop highly potent and long-acting GHRH antagonists for potential therapeutic use. These peptides contain the D-Arg 2 substitution that is known to produce predominantly GHRH antagonistic property when incorporated into the analogs of GHRH (9,10). Thus JV-1-36, JV-1-38, and JV-1-42 proved to be selective GHRH-R antagonists, because they bound to GHRH-R with high affinity and blocked the GH-releasing effect of GHRH in the pituitary cell superfusion system but were ineffective to inhibit VPAC 1 -R and VPAC 2 -R.…”

Section: Discussionmentioning

confidence: 99%

“…The first reported human GHRH (hGHRH) antagonist [Ac-Tyr 1 , D-Arg 2 ]hGHRH(1-29)NH 2 proved to be a weak VPAC-R agonist when tested on rat pancreatic membranes (8 -10). In contrast, another analog of GHRH [Ac-Tyr 1 , D-Phe 2 ]hGHRH(1-29)NH 2 had a pronounced VPAC-R inhibitory activity (8,10), and it also exerted a partial GHRH agonistic effect (9,10).…”

mentioning

confidence: 93%

“…Native GHRH has a low affinity to VPAC-R, whereas its synthetic derivatives have various affinities to these binding sites (7)(8)(9)(10). The first reported human GHRH (hGHRH) antagonist [Ac-Tyr 1 , D-Arg 2 ]hGHRH(1-29)NH 2 proved to be a weak VPAC-R agonist when tested on rat pancreatic membranes (8 -10).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Antagonistic actions of analogs related to growth hormone-releasing hormone (GHRH) on receptors for GHRH and vasoactive intestinal peptide on rat pituitary and pineal cells in vitro

Rékási¹,

Varga

Schally

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Peptide analogs of growth hormone-releasing hormone (GHRH) can potentially interact with vasoactive intestinal peptide (VIP) receptors (VPAC1-R and VPAC2-R) because of the structural similarities of these two hormones and their receptors. We synthesized four new analogs related to GHRH (JV-1-50, JV-1-51, JV-1-52, and JV-1-53) with decreased GHRH antagonistic activity and increased VIP antagonistic potency. To characterize various peptide analogs for their antagonistic activity on receptors for GHRH and VIP, we developed assay systems based on superfusion of rat pituitary and pineal cells. Receptor-binding affinities of peptides to the membranes of these cells were also evaluated by radioligand competition assays. Previously reported GHRH antagonists JV-1-36, JV-1-38, and JV-1-42 proved to be selective for GHRH receptors, because they did not influence VIP-stimulated VPAC 2 receptordependent prolactin release from pituitary cells or VPAC 1 receptordependent cAMP efflux from pinealocytes but strongly inhibited GHRH-stimulated growth hormone (GH) release. Analogs JV-1-50, JV-1-51, and JV-1-52 showed various degrees of VPAC 1-R and VPAC 2-R antagonistic potency, although also preserving a substantial GHRH antagonistic effect. Analog JV-1-53 proved to be a highly potent VPAC 1 and VPAC2 receptor antagonist, devoid of inhibitory effects on GHRH-evoked GH release. The antagonistic activity of these peptide analogs on processes mediated by receptors for GHRH and VIP was consistent with the binding affinity. The analogs with antagonistic effects on different types of receptors expressed on tumor cells could be utilized for the development of new approaches to treatment of various human cancers.growth hormone-releasing hormone and vasoactive intestinal peptide antagonists ͉ structure-activity relationships ͉ cancer therapy

show abstract

Rational design, synthesis, and biological evaluation of novel growth hormone releasing factor analogues

1995

View full text Add to dashboard Cite

Since its initial discovery in 1982, growth hormone-releasing factor (GRF) has been the subject of intense investigation. This interest was prompted by the potential application of GRF for stimulating growth in dwarf humans and for performance enhancement in livestock. Substantial research has been focused upon the development of potent, long-acting analogs as therapeutics. Herein is described a summary of the cumulative efforts of various laboratories endeavoring in this quest. The rationale utilized in GRF analog development is discussed: 1) determination of bioactive core, 2) evaluation of secondary structure, and 3) elucidation of degradation pathways (chemical and enzymatic). Using this information, several series of linear (unnatural and natural sequence) and cyclic GRF analogs were designed, synthesized, and evaluated. Stimulated by the constraints of commercial production, innovative, alternative methods of synthesis were explored: solid-phase, solution-phase, enzymatic, and recombinant. To date, the most promising candidate for drug development is [His1, Val2, Gln8, Ala15, Leu27]-hGRF(1-32)-OH. This natural sequence analog, consisting of rodent and human sequences, incorporates the bioactive core, preferred secondary structure, resistance to chemical and enzymatic degradation; with the added benefit of amenability to large-scale recombinant synthesis.

show abstract

Comparative structural requirements of thirty GRF analogs for interaction with GRF- and VIP receptors and coupling to adenylate cyclase in rat adenopituitary, liver and pancreas

Cited by 22 publications

References 26 publications

Structural requirements for the occupancy of pituitary adenylate‐cyclase‐activating‐peptide (PACAP) receptors and adenylate cyclase activation in human neuroblastoma NB‐OK‐1 cell membranes

Structural requirements for the occupancy of pituitary adenylate‐cyclase‐activating‐peptide (PACAP) receptors and adenylate cyclase activation in human neuroblastoma NB‐OK‐1 cell membranes

Antagonistic actions of analogs related to growth hormone-releasing hormone (GHRH) on receptors for GHRH and vasoactive intestinal peptide on rat pituitary and pineal cells in vitro

Rational design, synthesis, and biological evaluation of novel growth hormone releasing factor analogues

Contact Info

Product

Resources

About