Antagonists of Substance P from Emphasis on Position 11.

Folkers, Karl; Rosell, Sune; Jc, Xu; Björkroth, Ulla; Ya, LU; Yz, Liu

doi:10.3891/acta.chem.scand.37b-0623

Cited by 11 publications

(2 citation statements)

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“…Amino acid sequences in all SP related peptides are seen to be important for interaction but antagonists have resulted mainly from substitutions at positions 7 and 9. D-Trp seems to be the most favourable for antagonistic activity and Leu seems to add potency, [143] while D-Pro in position 2 is found to be nonessential.…”

Section: Structure Activity Relationships Of Sp and Its Analogsmentioning

confidence: 96%

Substance P: Structure, Function, and Therapeutics

Datar

Srivastava²,

Coutinho³

et al. 2004

CTMC

148

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Extensive efforts since 1931, on the structural determination of the mammalian tachykinin SP by NMR, CD and IR have turned out to be inconclusive. Studies are now being concentrated on the structural properties and characteristics of various NK receptors (NK(1), NK(2) and NK(3)) with the help of genetics, cloning, receptor engineering, mutagenesis and modeling. This knowledge is now being fruitfully used in the development of non-peptide NK(1) receptor antagonists that essentially block the pharmacological effects of SP. It is now being realized that the simultaneous blockade of two or more receptors gives promising results in emesis, depression and pulmonary obstructive diseases. In addition to the synthetic compounds, the discovery of antagonists from natural origin has added a great value to this field. In this review we have made an attempt to present the structural characteristics of SP, its analogs and antagonists, the structural characteristics of the NK receptor, and structure activity relationships that have helped to improve the therapeutic utilities of SP antagonists.

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Section: Structure Activity Relationships Of Sp and Its Analogsmentioning

confidence: 96%

Substance P: Structure, Function, and Therapeutics

Datar

Srivastava²,

Coutinho³

et al. 2004

CTMC

148

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“…Antagonists have resulted from substitutions in positions 7 and 9. D-Tryptophan in these positions seems to be favourable for antagonistic activity and leucine in position 11 seems to add potency (Folkers et al, 1983). D-Proline in position 2 is not essential.…”

Section: ! Cmentioning

confidence: 98%

Biological evaluation of substance P antagonists

Folkers

Håkanson

Hörig

et al. 1984

British J Pharmacology

Self Cite

191

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1 Five undeca-and six C-terminal heptapeptide substance P (SP) analogues were tested for their capacity to block the contractile effect of SP on the guinea-pig isolated taenia coli. They had one feature in common, namely substitutions in positions 7 and 9 in the SP molecule. In the majority of analogues D-tryptophan was used for these substitutions. 2 All analogues tested were found to be competitive antagonists to exogenous SP and to be capable of blocking the electrically induced non-cholinergic, non-adrenergic neuronal contraction of the taenia. (Spantide) had the highest pA2 value, 7.1 -7.2, and the lowest IC50 value, 10-6 M. The pA2 values of the heptapeptides were generally lower. 4 Three of the most potent antagonists were tested for specificity and found to block the smooth muscle contraction induced by SP, physalaemin, eledoisin and bombesin but not that induced by bradykinin, carbachol, 5-hydroxytryptamine, histamine, prostaglandins and vasopressin. 5 The SP antagonists were also tested for spasmogenic effect on the taenia and for their capacity to release histamine from rat isolated peritoneal mast cells. The spasmogenic activity displayed by most of the SP antagonists tested is likely to be related to their ability to release histamine since the contractile response was reduced by mepyramine, a histamine Hl-receptor antagonist.6 (D-Arg', D-Trp7 9, Leutt) SP was notable for combining a high antagonistic potency with a weak spasmogenic effect (and poor histamine releasing effect). IntroductionMethods

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