A Sonogashira coupling strategy was employed to synthesize a new series of allosteric modulators for the A1 adenosine receptor based on the 2-amino-3-(p-chlorobenzoyl)-4-substituted 5-thiophene skeleton, with a two-carbon (rigid or flexible) linker between the 5-position of the thiophene ring and a (hetero)aryl or alkyl moiety. Among the compounds characterized by the presence of a common phenylacetylene moiety at the 5-position of the thiophene ring, the neopentyl substitution at the 4-position supported a strong activity. In the series of 4-neopentyl derivatives, the presence of an acetylene spacer at the 5-position of the thiophene is optimal for activity, while reduction of the acetylene to an ethyl moiety decreased activity, both in functional and binding assays. Derivatives 4e, 4g-h, 4j, 4l and 4m were the most promising compounds in binding (saturation and competition) and functional cAMP studies, being able to potentiate agonist [3H]CCPA binding to the A1 receptor, with 4e as the best compound of the series. The latter compound also retarded the dissociation of another radiolabeled agonist, [3H]NECA, from the receptor.

Synthesis and Biological Evaluation of Novel Allosteric Enhancers of the A1 Adenosine Receptor Based on 2-Amino-3-(4’-Chlorobenzoyl)-4-Substituted-5-Arylethynyl Thiophene

ROMAGNOLI, Romeo;BARALDI, Pier Giovanni;SAPONARO, Giulia;PRETI, Delia;AGHAZADEH TABRIZI, Mojgan;BARALDI, Stefania;VINCENZI, Fabrizio;BOREA, Pier Andrea;VARANI, Katia
2014

Abstract

A Sonogashira coupling strategy was employed to synthesize a new series of allosteric modulators for the A1 adenosine receptor based on the 2-amino-3-(p-chlorobenzoyl)-4-substituted 5-thiophene skeleton, with a two-carbon (rigid or flexible) linker between the 5-position of the thiophene ring and a (hetero)aryl or alkyl moiety. Among the compounds characterized by the presence of a common phenylacetylene moiety at the 5-position of the thiophene ring, the neopentyl substitution at the 4-position supported a strong activity. In the series of 4-neopentyl derivatives, the presence of an acetylene spacer at the 5-position of the thiophene is optimal for activity, while reduction of the acetylene to an ethyl moiety decreased activity, both in functional and binding assays. Derivatives 4e, 4g-h, 4j, 4l and 4m were the most promising compounds in binding (saturation and competition) and functional cAMP studies, being able to potentiate agonist [3H]CCPA binding to the A1 receptor, with 4e as the best compound of the series. The latter compound also retarded the dissociation of another radiolabeled agonist, [3H]NECA, from the receptor.
2014
Romagnoli, Romeo; Baraldi, Pier Giovanni; A. P., Ijzerman; A., Massink; O., Cruz Lopez; L. C., Lopez Cara; Saponaro, Giulia; Preti, Delia; AGHAZADEH TABRIZI, Mojgan; Baraldi, Stefania; A. R., Moorman; Vincenzi, Fabrizio; Borea, Pier Andrea; Varani, Katia
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/2120612
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 23
  • ???jsp.display-item.citation.isi??? 22
social impact