Structure-Activity studies on position 14 of human α-calcitonin gene- related peptide

Jianzhong Li, James E. Matsuura, David J J Waugh, Thomas E. Adrian, Peter W. Abel, Mark C. Manning, D. David Smith

Research output: Contribution to journalArticle

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Abstract

A structure-activity study was performed to examine the role of position 14 of human α-calcitonin gene-related peptide (h-α-CGRP) in activating the receptor. Interestingly, position 14 of h-α-CGRP contains a glycyl residue and is part of an α-helix spanning residues 8-18. Analogues [Ala14]-h-α- CGRP, [Aib14]-h-α-CGRP, [Asp14]-h-α-CGRP, [Asn14]-h-α-CGRP, and [Pro14]-h-α-CGRP were synthesized by solid phase peptide methodology and purified by RP-HPLC. Secondary structure was measured by circular dichroism spectroscopy. Agonist activities were determined as the analogues ability to stimulate amylase secretion form guinea pig pancreatic acini and to relax precontracted porcine coronary arteries. Analogues [Ala14]-h-α-CGRP, [Aib14]-h-α-CGRP, [Asp14]-h-α-CGRP, and [Asn14]-h-α-CGRP, all containing residues with a high helical propensity in position 14, were potent full agonists compared to h-α-CGRP in both tissues. Interestingly, replacement of Gly14 of h-α-CGRP with these residues did not substantially increase the helical content of these analogues. [Pro14]-h-α-CGRP, predictably, has significantly lower helical content and is a 20-fold less potent agonist on coronary artery, known to contain CGRP-1 receptor subtypes, and an antagonist on pancreatic acini, known to contain CGRP-2 receptor subtypes. In conclusion, the residue in position 14 plays a structural role in stabilizing the α-helix spanning residues 8-18. The α-helix is crucial for maintaining highly potent agonist effects of h-α-CGRP at CGRP receptors. The wide variety of functional groups that can be tolerated in position 14 with no substantial modification of agonist effects suggests the residue in this position is not in contact with the CGRP receptor. [Pro14]-h-α-CGRP may be a useful pharmacological tool to distinguish between CGRP-1 and CGRP- 2 receptor subtypes.

Original languageEnglish
Pages (from-to)3071-3076
Number of pages6
JournalJournal of Medicinal Chemistry
Volume40
Issue number19
DOIs
StatePublished - 1997
Externally publishedYes

Fingerprint

Calcitonin Gene-Related Peptide
Calcitonin Gene-Related Peptide Receptors
Coronary Vessels
Circular dichroism spectroscopy
Amylases
Circular Dichroism
Functional groups

All Science Journal Classification (ASJC) codes

  • Organic Chemistry

Cite this

Li, J., Matsuura, J. E., Waugh, D. J. J., Adrian, T. E., Abel, P. W., Manning, M. C., & Smith, D. D. (1997). Structure-Activity studies on position 14 of human α-calcitonin gene- related peptide. Journal of Medicinal Chemistry, 40(19), 3071-3076. https://doi.org/10.1021/jm9608164

Structure-Activity studies on position 14 of human α-calcitonin gene- related peptide. / Li, Jianzhong; Matsuura, James E.; Waugh, David J J; Adrian, Thomas E.; Abel, Peter W.; Manning, Mark C.; Smith, D. David.

In: Journal of Medicinal Chemistry, Vol. 40, No. 19, 1997, p. 3071-3076.

Research output: Contribution to journalArticle

Li, J, Matsuura, JE, Waugh, DJJ, Adrian, TE, Abel, PW, Manning, MC & Smith, DD 1997, 'Structure-Activity studies on position 14 of human α-calcitonin gene- related peptide', Journal of Medicinal Chemistry, vol. 40, no. 19, pp. 3071-3076. https://doi.org/10.1021/jm9608164
Li, Jianzhong ; Matsuura, James E. ; Waugh, David J J ; Adrian, Thomas E. ; Abel, Peter W. ; Manning, Mark C. ; Smith, D. David. / Structure-Activity studies on position 14 of human α-calcitonin gene- related peptide. In: Journal of Medicinal Chemistry. 1997 ; Vol. 40, No. 19. pp. 3071-3076.
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title = "Structure-Activity studies on position 14 of human α-calcitonin gene- related peptide",
abstract = "A structure-activity study was performed to examine the role of position 14 of human α-calcitonin gene-related peptide (h-α-CGRP) in activating the receptor. Interestingly, position 14 of h-α-CGRP contains a glycyl residue and is part of an α-helix spanning residues 8-18. Analogues [Ala14]-h-α- CGRP, [Aib14]-h-α-CGRP, [Asp14]-h-α-CGRP, [Asn14]-h-α-CGRP, and [Pro14]-h-α-CGRP were synthesized by solid phase peptide methodology and purified by RP-HPLC. Secondary structure was measured by circular dichroism spectroscopy. Agonist activities were determined as the analogues ability to stimulate amylase secretion form guinea pig pancreatic acini and to relax precontracted porcine coronary arteries. Analogues [Ala14]-h-α-CGRP, [Aib14]-h-α-CGRP, [Asp14]-h-α-CGRP, and [Asn14]-h-α-CGRP, all containing residues with a high helical propensity in position 14, were potent full agonists compared to h-α-CGRP in both tissues. Interestingly, replacement of Gly14 of h-α-CGRP with these residues did not substantially increase the helical content of these analogues. [Pro14]-h-α-CGRP, predictably, has significantly lower helical content and is a 20-fold less potent agonist on coronary artery, known to contain CGRP-1 receptor subtypes, and an antagonist on pancreatic acini, known to contain CGRP-2 receptor subtypes. In conclusion, the residue in position 14 plays a structural role in stabilizing the α-helix spanning residues 8-18. The α-helix is crucial for maintaining highly potent agonist effects of h-α-CGRP at CGRP receptors. The wide variety of functional groups that can be tolerated in position 14 with no substantial modification of agonist effects suggests the residue in this position is not in contact with the CGRP receptor. [Pro14]-h-α-CGRP may be a useful pharmacological tool to distinguish between CGRP-1 and CGRP- 2 receptor subtypes.",
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AU - Li, Jianzhong

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AU - Abel, Peter W.

AU - Manning, Mark C.

AU - Smith, D. David

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N2 - A structure-activity study was performed to examine the role of position 14 of human α-calcitonin gene-related peptide (h-α-CGRP) in activating the receptor. Interestingly, position 14 of h-α-CGRP contains a glycyl residue and is part of an α-helix spanning residues 8-18. Analogues [Ala14]-h-α- CGRP, [Aib14]-h-α-CGRP, [Asp14]-h-α-CGRP, [Asn14]-h-α-CGRP, and [Pro14]-h-α-CGRP were synthesized by solid phase peptide methodology and purified by RP-HPLC. Secondary structure was measured by circular dichroism spectroscopy. Agonist activities were determined as the analogues ability to stimulate amylase secretion form guinea pig pancreatic acini and to relax precontracted porcine coronary arteries. Analogues [Ala14]-h-α-CGRP, [Aib14]-h-α-CGRP, [Asp14]-h-α-CGRP, and [Asn14]-h-α-CGRP, all containing residues with a high helical propensity in position 14, were potent full agonists compared to h-α-CGRP in both tissues. Interestingly, replacement of Gly14 of h-α-CGRP with these residues did not substantially increase the helical content of these analogues. [Pro14]-h-α-CGRP, predictably, has significantly lower helical content and is a 20-fold less potent agonist on coronary artery, known to contain CGRP-1 receptor subtypes, and an antagonist on pancreatic acini, known to contain CGRP-2 receptor subtypes. In conclusion, the residue in position 14 plays a structural role in stabilizing the α-helix spanning residues 8-18. The α-helix is crucial for maintaining highly potent agonist effects of h-α-CGRP at CGRP receptors. The wide variety of functional groups that can be tolerated in position 14 with no substantial modification of agonist effects suggests the residue in this position is not in contact with the CGRP receptor. [Pro14]-h-α-CGRP may be a useful pharmacological tool to distinguish between CGRP-1 and CGRP- 2 receptor subtypes.

AB - A structure-activity study was performed to examine the role of position 14 of human α-calcitonin gene-related peptide (h-α-CGRP) in activating the receptor. Interestingly, position 14 of h-α-CGRP contains a glycyl residue and is part of an α-helix spanning residues 8-18. Analogues [Ala14]-h-α- CGRP, [Aib14]-h-α-CGRP, [Asp14]-h-α-CGRP, [Asn14]-h-α-CGRP, and [Pro14]-h-α-CGRP were synthesized by solid phase peptide methodology and purified by RP-HPLC. Secondary structure was measured by circular dichroism spectroscopy. Agonist activities were determined as the analogues ability to stimulate amylase secretion form guinea pig pancreatic acini and to relax precontracted porcine coronary arteries. Analogues [Ala14]-h-α-CGRP, [Aib14]-h-α-CGRP, [Asp14]-h-α-CGRP, and [Asn14]-h-α-CGRP, all containing residues with a high helical propensity in position 14, were potent full agonists compared to h-α-CGRP in both tissues. Interestingly, replacement of Gly14 of h-α-CGRP with these residues did not substantially increase the helical content of these analogues. [Pro14]-h-α-CGRP, predictably, has significantly lower helical content and is a 20-fold less potent agonist on coronary artery, known to contain CGRP-1 receptor subtypes, and an antagonist on pancreatic acini, known to contain CGRP-2 receptor subtypes. In conclusion, the residue in position 14 plays a structural role in stabilizing the α-helix spanning residues 8-18. The α-helix is crucial for maintaining highly potent agonist effects of h-α-CGRP at CGRP receptors. The wide variety of functional groups that can be tolerated in position 14 with no substantial modification of agonist effects suggests the residue in this position is not in contact with the CGRP receptor. [Pro14]-h-α-CGRP may be a useful pharmacological tool to distinguish between CGRP-1 and CGRP- 2 receptor subtypes.

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