Synthesis and biological activities of analogs of the luteinizing hormone-releasing hormone (LH-RH) modified in position 2

Rees, R. W.; Foell, Theodore; Chai, Sie-Yearl; Grant, Norman H.

doi:10.1021/jm00255a025

Cited by 53 publications

(12 citation statements)

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“…In fact, while [Des-His'ILH-RH inhibits 50% of LH-RH action at a molar ratio of 3000, [D-P~~']LH-RH leads to the same effect at a molar ratio of approximately 1000 (Table 1). This modification at position 2 was first suggested by Rees et al (1974) who reported that [D-P~~']LH-RH was a good in vitro inhibitor of LH-RH. The same potency ratio applies to the D-leucine and D-phenylalanine substituted compounds at position 6, the [~-Phe*] analogues being approximately three times more potent than the corresponding [Des-His'] derivatives (Table 1).…”

Section: Discussionmentioning

confidence: 73%

INHIBITORY ACTIVITY OF ANALOGUES OF LUTEINIZING HORMONE‐RELEASING HORMONE (LH‐RH) IN VITRO AND IN VIVO

Ferland¹,

Labrie²,

Savary³

et al. 1976

Clinical Endocrinology

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Improved inhibitors of LH-RH are those which, beside removal of the histidine residue at position 2 of LH-RH, include replacement of glycine at position 6 by a D-amino acid. A still better modification is replacement of the histidine residue at position 2 by D-phenylalanine. As examples, when tested in pituitary cells in culture, [Des-His2]LH-RH, [Des-His2, D-Leu6]LH-RH, [Des-His2, D-Phe6]-LH-RH, [D-Phe2]LH-RH, [D-Phe2, D-Leu6]LH-RH and [D-Phe2, D-Phe6]LH-RH inhibit 50% of LH release induced by LH-RH at molar ratios (MR50S) of 3000, 500, 60, 1000, 150 and 25, respectively. [D-Phe2, D-Phe6, D-Phe7]LH-RH, [D-Phe2, Phe3, D-Phe6]LH-RH and [D-Phe2, Phe5, D-Phe6]LH-RH have MR50 values of respectively 400, 100, and 75. When evaluated in vivo, some of the mentioned structural modifications permit inhibition of LH-RH action at molar ratios lower than observed in vitro. At a 500 molar ratio, [D-Phe2, Phe5, D-Phe6]-LH-RH inhibits the plasma LH rise induced by LH-RH by 75% up to 5 h after its injection. When administered at 12.00 hours at the dose of 2 mg, this analogue inhibits the spontaneous pro-oestrus LH surge and ovulation by 85 and 75%, respectively.

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Section: Discussionmentioning

confidence: 73%

INHIBITORY ACTIVITY OF ANALOGUES OF LUTEINIZING HORMONE‐RELEASING HORMONE (LH‐RH) IN VITRO AND IN VIVO

Ferland¹,

Labrie²,

Savary³

et al. 1976

Clinical Endocrinology

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“…If the binding activity is retained, the resulting compound may be a potent receptor antagonist. For LHRH analogues it was demonstrated that substitution of amino acids such as (D-Phe) for histidine at the 2 position resulted in analogues which functioned as LHRH antagonists (Rees et al, 1978;Vale et al, 1972). Here a similar strategy was utilized to generate BN receptor antagonists.…”

Section: Discussionmentioning

confidence: 99%

(D‐Phe¹²) bombesin and substance P analogues function as central bombesin receptor antagonists

Merali¹,

Merchant²,

Crawley³

et al. 1988

Synapse

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The potency of synthetic bombesin (BN) analogues with D-Phe12 substitutions and substance P analogues was investigated in the rat CNS. (D-Phe12,Leu14)BN, (D-Phe12)BN and (Tyr4,D-Phe12)BN inhibited binding to rat brain slices with IC50 values of approximately 2 microM. Similarly, spantide inhibited binding to rat brain slices with an IC50 value of 1.5 microM. Spantide inhibited specific (125I-Tyr4)BN binding as a result of decreased rate of association, whereas the rate of dissociation was unaffected. Neither the (D-Phe12)BN analogues nor the substance P analogues inhibited specific binding of 125I-VIP to rat brain slices. Central administration of BN (0.5 micrograms) induced grooming and suppressed feeding and resting. (Tyr4, D-Phe12)BN (5 micrograms) antagonized the behavioral effects of BN. Although spantide (2 micrograms) also antagonized many of the BN effects, it had intrinsic effects and hence the behavioral antagonism was not specific. These data suggest that although both (D-Phe12)BN and substance P analogues may function as central BN receptor antagonists, the (D-Phe12)BN analogues may be functionally the more useful class of antagonists.

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“…We reported earlier (Monahan et al, 1973b) that [D-A~~']LRF was also an antagonist. Rees et al (1974) found that [ D -P~~~I L R F was several times more potent an antagonist than des-His2-LRF. In confirmation of their results we observe [ D -P~~~I L R F to have a potency of 0.4 compared to des-His2-LRF at 0.15.…”

Section: Relativementioning

confidence: 99%

Pharmacology of Hypothalamic Regulatory Peptides

Vale

Rivier

Brown

et al. 1976

Clinical Endocrinology

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Synthesis and biological activities of analogs of the luteinizing hormone-releasing hormone (LH-RH) modified in position 2

Cited by 53 publications

References 3 publications

INHIBITORY ACTIVITY OF ANALOGUES OF LUTEINIZING HORMONE‐RELEASING HORMONE (LH‐RH) IN VITRO AND IN VIVO

INHIBITORY ACTIVITY OF ANALOGUES OF LUTEINIZING HORMONE‐RELEASING HORMONE (LH‐RH) IN VITRO AND IN VIVO

(D‐Phe¹²) bombesin and substance P analogues function as central bombesin receptor antagonists

Pharmacology of Hypothalamic Regulatory Peptides

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Synthesis and biological activities of analogs of the luteinizing hormone-releasing hormone (LH-RH) modified in position 2

Cited by 53 publications

References 3 publications

INHIBITORY ACTIVITY OF ANALOGUES OF LUTEINIZING HORMONE‐RELEASING HORMONE (LH‐RH) IN VITRO AND IN VIVO

INHIBITORY ACTIVITY OF ANALOGUES OF LUTEINIZING HORMONE‐RELEASING HORMONE (LH‐RH) IN VITRO AND IN VIVO

(D‐Phe12) bombesin and substance P analogues function as central bombesin receptor antagonists

Pharmacology of Hypothalamic Regulatory Peptides

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(D‐Phe¹²) bombesin and substance P analogues function as central bombesin receptor antagonists