Synthesis of Substance P Analogs and Agonistic and Antagonistic Activities.

Leban, Johann; Rackur, Gerhard; Yamaguchi, Isomaro; Folkers, Karl; Björkroth, Ulla; Rosell, Sune; Yanaihara, Noboru; Yanaihara, Chizuko

doi:10.3891/acta.chem.scand.33b-0664

Cited by 25 publications

(21 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…At the molecular level, most of these antagonists appear to interact fully or partially with the binding domain of SP and to share at least one aromatic moiety in their structure (8). Preceding this profusion of small antagonist molecules, two major generations of peptidic antagonists had been proposed: peptides with d ‐amino acids, substituted with at least one d ‐Trp (8–10) and peptides with a β‐turn type II′ constraint (8–12), such as a spirolactam moiety (11). Studies with NK‐1 receptor mutants suggested that the nonpeptidic and the peptidic antagonists bind the receptor in a manner analogous to SP (13–15).…”

mentioning

confidence: 99%

Analogs of Substance P modified at the C‐terminus which are both agonist and antagonist of the NK‐1 receptor depending on the second messenger pathway

Sachon¹,

Girault-Lagrange²,

Chassaing³

et al. 2002

The Journal of Peptide Research

View full text Add to dashboard Cite

The initial goal of this study was to analyze, using photolabeling, the interactions between Substance P and its tachykinin NK-1 receptor. Therefore, the photoreactive amino acid para-benzoyl-phenylalanine (pBzl)Phe was incorporated into the Substance P sequence from position 4 to 11 leading to Bapa0[(pBzl)Phex]SP analogs. Biotinyl sulfone-5-aminopentanoic acid (Bapa) was introduced in order to purify the covalent complex. These photoreactive SP analogs were first assayed for their affinity for the two binding sites associated with the NK-1 receptor, as well as for their potency in activating the phospholipase C and adenylate cyclase pathways. All analogs photoreactive from position 4 to 11 have moderate to high affinity for the two NK-1 receptor-binding sites, except for the analog modified at position 7. This affinity could be correlated to their potency to activate the phospholipase C and adenylate cyclase pathways, except for the analog photoreactive at position 11. Bapa0[(pBzl)Phe11]SP was found to be an agonist in the phospholipase C pathway and an antagonist in the adenylate cyclase pathway, other analogs modified at position 11 were therefore analyzed. Among these, Bapa0[Pro9, (pBzl)Hcy(O2)11]SP is a partial agonist, whereas Bapa0[Hcy(ethylaminodansyl)11]SP is a full agonist in the phospholipase C pathway, the two analogs being antagonist in the adenylate cyclase pathway. These results show that analogs of SP can be simultaneously agonist at one binding site and antagonist at the other binding site associated with the NK-1 receptor.

show abstract

mentioning

confidence: 99%

Analogs of Substance P modified at the C‐terminus which are both agonist and antagonist of the NK‐1 receptor depending on the second messenger pathway

Sachon¹,

Girault-Lagrange²,

Chassaing³

et al. 2002

The Journal of Peptide Research

View full text Add to dashboard Cite

show abstract

“…The great majority of the pharmacological (particularly the structure-activity) studies on SP have been carried out only in the intesti nal smooth muscle of the guinea pig ileum [Yajima et al, 1973;Bergmann et al" 1974a, b;Bury and Mashford, 1976;Yanahiara et al, 1977a, b: Rosell et al" 1977Leban et al, 1979;Chipkin et al, 1979], despite the fact that SP is active on isolated vessels of several animals.…”

Section: Introductionmentioning

confidence: 99%

Mini Review: Smooth Muscle Pharmacology of Substance P

Couture

Regoli²

1982

Pharmacology

View full text Add to dashboard Cite

Substance P (SP), some of its C-terminal fragments and some of its homologues (physalaemin and eledoisin) are hypotensive in rats anaesthetised with urethane, vasodilators in isolated rabbit hearts, inhibitors of noradrenaline-induced contractions of the dog carotid artery and stimulants of contractions of the rabbit mesenteric vein, the guinea pig ileum and the rat colon. The effects of these peptides appear to be due to a direct action, mediated by specific receptors, in 4 of the 6 preparations, while the stimulation of the guinea pig ileum may depend in part on the release of intramural acetylcholine, because it is partially antagonised by atropine, and catecholamines appear to interfere with the contractile response of the rat colon to SP, since this response is potentiated by propranolol. SP, its C-terminal fragments, physalaemin and eledoisin appear to activate the same receptors systems in 4 of the 5 preparations in which desensitisation experiments could be performed (namely the rat blood pressure, the isolated rabbit heart, the rabbit mesenteric vein and the guinea pig ileum). In the dog carotid artery, there was no cross-desensitisation between SP and eledoisin but only between SP, its C-terminal fragments and physalaemin. The rat colon could not be desensitised.

show abstract

“…The idea was first raised in 1979 in relation to the effects of SP agonists in the guinea pig ileum. 52 In 1981, Folkers et al 53 proposed a chemical design of SP antagonists. Engberg et al 54 then developed the first synthetic peptide antagonist for use in the CNS, before the first nonpeptide SP antagonist was developed 10 years later by Snider et al 55 in the form of CP-96,345, a potent and highly selective antagonist of the NK 1 receptor.…”

Section: Nk 1 Receptor Antagonistsmentioning

confidence: 99%

Substance P Antagonists as a Therapeutic Approach to Improving Outcome Following Traumatic Brain Injury

Vink

Heuvel

2010

Neurotherapeutics

View full text Add to dashboard Cite

Summary:Although a number of secondary injury factors are known to contribute to the development of morphological injury and functional deficits following traumatic brain injury, accumulating evidence has suggested that neuropeptides, and in particular substance P, may play a critical role. Substance P is released early following acute injury to the CNS as part of a neurogenic inflammatory response. In so doing, it facilitates an increase in the permeability of the bloodbrain barrier and the development of vasogenic edema. At the cellular level, substance P has been shown to directly result in neuronal cell death; functionally, substance P has been implicated in learning and memory, mood and anxiety, stress mechanisms, emotion-processing, migraine, emesis, pain, and seizures, all of which may be adversely affected after brain injury. Inhibition of post-traumatic substance P activity, either by preventing release or by antagonism of the neurokinin-1 receptor, has consistently resulted in a profound decrease in development of edema and marked improvements in functional outcome. This review summarizes the current evidence supporting a role for substance P in acute brain injury.

show abstract

Synthesis of Substance P Analogs and Agonistic and Antagonistic Activities.

Cited by 25 publications

References 0 publications

Analogs of Substance P modified at the C‐terminus which are both agonist and antagonist of the NK‐1 receptor depending on the second messenger pathway

Analogs of Substance P modified at the C‐terminus which are both agonist and antagonist of the NK‐1 receptor depending on the second messenger pathway

Mini Review: Smooth Muscle Pharmacology of Substance P

Substance P Antagonists as a Therapeutic Approach to Improving Outcome Following Traumatic Brain Injury

Contact Info

Product

Resources

About