SSR240600 [(<i>R</i>)-2-(1-{2-[4-{2-[3,5-Bis(trifluoromethyl)phenyl]acetyl}-2-(3,4-dichlorophenyl)-2-morpholinyl]ethyl}- 4-piperidinyl)-2-methylpropanamide], a Centrally Active Nonpeptide Antagonist of the Tachykinin Neurokinin-1 Receptor: I. Biochemical and Pharmacological Characterization

Emonds‐Alt, Xavier; Proietto, Vincenzo; Steinberg, R.; Oury-Donat, Florence; Vigé, Xavier; Vilain, P.; Naline, Emmanuel; Daoui, Samira; Advenier, C.; Fur, G. Le; Maffrand, Jean‐Pierre; Soubrié, Philippe; Pascal, Marc

doi:10.1124/jpet.102.040162

Cited by 19 publications

(6 citation statements)

References 39 publications

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“…2002). Due to the main involvement of the tachykinin new NK 1 ‐sensitive receptors in this regulation, solely the tachykinin antagonists having a high affinity for these receptors such as SR140333, GR205171 and particularly SSR240600, a central active non‐peptide antagonist (Emonds‐Alt et al . 2002; Steinberg et al .…”

Section: Discussionmentioning

confidence: 99%

“…As endogenous tachykinins participate to the excess of cholinergic transmission observed under deficiency of the dopaminergic neurones, we have proposed the use of selective tachykinin NK 1 , NK 2 or NK 3 antagonists as indirect anti-cholinergic compounds in the treatment of Parkinson's disease (Kemel et al 2002). Due to the main involvement of the tachykinin new NK 1 -sensitive receptors in this regulation, solely the tachykinin antagonists having a high affinity for these receptors such as SR140333, GR205171 and particularly SSR240600, a central active non-peptide antagonist (Emonds-Alt et al 2002;Steinberg et al 2002), could be preferentially used as indirect anticholinergic drugs.…”

Section: Discussionmentioning

confidence: 99%

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The new neurokinin 1‐sensitive receptor mediates the facilitation by endogenous tachykinins of the NMDA‐evoked release of acetylcholine after suppression of dopaminergic transmission in the matrix of the rat striatum

Kemel

Pérez

Beaujouan

et al. 2003

Journal of Neurochemistry

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Using an in vitro microsuperfusion procedure, the NMDAevoked release of [ 3 H]ACh was studied after suppression of dopamine (DA) transmission (a-methyl-p-tyrosine) in striatal compartments of the rat. ]substance P but also by neurokinin A and neuropeptide K (1 nM each). According to the rank order of potency of agonists for counteracting the antagonist responses ([Pro 9 ]substance P, 0.013 nM > neurokinin A, 0.15 nM ? substance P(6-11) 7.7 nM ¼ septide 8.7 nM), the new NK 1 -sensitive receptors mediate the facilitation by endogenous tachykinins of the NMDA-evoked release of ACh in the matrix, after suppression of DA transmission. Solely the NK 1 antagonists having a high affinity for these receptors could be used as indirect anti-cholinergic agents.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The new neurokinin 1‐sensitive receptor mediates the facilitation by endogenous tachykinins of the NMDA‐evoked release of acetylcholine after suppression of dopaminergic transmission in the matrix of the rat striatum

Kemel

Pérez

Beaujouan

et al. 2003

Journal of Neurochemistry

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“…An attempt by Sanofi at the development of a novel NK 1 antagonist resulted in SSR‐240600 ( 87 ), somewhat structurally related to 86 . Substance P was displaced from the NK 1 receptor by 87 with an IC 50 = 0.66 nM, whereas the NK 2 and NK 3 native ligands were displaced, respectively, at 3 and 4 orders of magnitude higher concentration of 87 .…”

Section: Pharmacological Activity Of Morpholine Derivatives On Varioumentioning

confidence: 99%

Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules

Kourounakis

Xanthopoulos

Tzara

2019

Medicinal Research Reviews

187

114

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Morpholine is a heterocycle featured in numerous approved and experimental drugs as well as bioactive molecules. It is often employed in the field of medicinal chemistry for its advantageous physicochemical, biological, and metabolic properties, as well as its facile synthetic routes. The morpholine ring is a versatile and readily accessible synthetic building block, it is easily introduced as an amine reagent or can be built according to a variety of available synthetic methodologies. This versatile scaffold, appropriately substituted, possesses a wide range of biological activities. There are many examples of molecular targets of morpholine bioactive in which the significant contribution of the morpholine moiety has been demonstrated; it is an integral component of the pharmacophore for certain enzyme active‐site inhibitors whereas it bestows selective affinity for a wide range of receptors. A large body of in vivo studies has demonstrated morpholine's potential to not only increase potency but also provide compounds with desirable drug‐like properties and improved pharamacokinetics. In this review we describe the medicinal chemistry/pharmacological activity of morpholine derivatives on various therapeutically related molecular targets, attempting to highlight the importance of the morpholine ring in drug design and development as well as to justify its classification as a privileged structure.

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“…They recently reported on the pharmacological and biochemical characterisation of this compound, where it was reported to inhibit citric acid-induced cough in guinea-pigs [117,118].…”

Section: Competitive Environmentmentioning

confidence: 99%

Potential therapeutic targets for neurokinin-1 receptor antagonists

Duffy¹

2004

Expert Opinion on Emerging Drugs

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The peptide substance P and its tachykinin receptor, neurokinin-1 (NK1), have been the focus of considerable research for their role in a variety of both central and peripheral diseases. Recent preclinical data, as well as relevant clinical findings, support the potential therapeutic value of NK1 receptor antagonists in centrally mediated disease states, including anxiety and depression. In addition, a separate body of literature supports the use of NK1 receptor antagonists as inhibitors of centrally mediated emetic and cough responses. The role of NK1 receptor antagonists as analgesic agents with potential to treat migraine headache has also been investigated. NK1 receptors are also found in a number of peripheral regions, including the bladder, gastrointestinal tract and bone marrow. Preclinical models have been employed to address the potential therapeutic uses for NK1 receptor antagonists in diseases associated with inflammatory responses, including asthma, irritable bowel syndrome and cystitis of the bladder. Finally, other more recent publications suggest a role for NK1 receptor antagonists as tumour suppressants and haematopoietic agents. These applications for NK1 receptor antagonists are discussed in this review.

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SSR240600 [(R)-2-(1-{2-[4-{2-[3,5-Bis(trifluoromethyl)phenyl]acetyl}-2-(3,4-dichlorophenyl)-2-morpholinyl]ethyl}- 4-piperidinyl)-2-methylpropanamide], a Centrally Active Nonpeptide Antagonist of the Tachykinin Neurokinin-1 Receptor: I. Biochemical and Pharmacological Characterization

Cited by 19 publications

References 39 publications

The new neurokinin 1‐sensitive receptor mediates the facilitation by endogenous tachykinins of the NMDA‐evoked release of acetylcholine after suppression of dopaminergic transmission in the matrix of the rat striatum

The new neurokinin 1‐sensitive receptor mediates the facilitation by endogenous tachykinins of the NMDA‐evoked release of acetylcholine after suppression of dopaminergic transmission in the matrix of the rat striatum

Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules

Potential therapeutic targets for neurokinin-1 receptor antagonists

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