TRP Channels pp 207-221 | Cite as

Drug Discovery for Soft Drugs on TRPV1 and TRPM8 Channels Using the Passerini Reaction

  • Tracey Pirali
  • Ubaldina Galli
  • Marta Serafini
  • Alessia Griglio
  • Armando A. Genazzani
  • Gian Cesare TronEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1987)


Multicomponent transformations, such as Ugi and Passerini reactions, allow for the fast synthesis of libraries of medium complexity, avoiding the formation of waste residues and significantly reducing time and money expenditure. Although the Ugi reaction has found a vast number of uses in medicinal chemistry, the employment of the Passerini reaction has received scant attention due to the formation of an α-acyloxyamide, which hardly resists the hydrolytic enzymes in the body. On the other hand, an overlooked possibility with the Passerini products is to exploit the presence of an ester group in the design and synthesis of soft drugs. We started to fill this gap, designing and synthesizing a series of TRPV1 and TRPM8 agonists able to act as soft drugs by using the Passerini reaction.

Key words

TRPV1 TRPM8 Passerini reaction Isocyanide Multicomponent reactions Soft drugs 



Financial support from Università del Piemonte Orientale—Novara—Italy and from Compagnia di San Paolo (Grant No. C61J12000280007) is acknowledged.


  1. 1.
    Zhu J, Wang Q, Wang M-X (2015) Multicomponent reactions in organic synthesis. Wiley-VCH Verlag GmbH & Co., WeinheimGoogle Scholar
  2. 2.
    Nenajdenko VG (2012) Isocyanide chemistry: applications in synthesis and material science. Wiley-VCH Verlag GmbH & Co., WeinheimCrossRefGoogle Scholar
  3. 3.
    Passerini M (1921) Sopra gli Isonitrili (I). Composto del p-Isonitrilazobenzolo con Acetone ed Acido Acetico. Gazz Chim Ital 51:126–129Google Scholar
  4. 4.
    Ugi I, Meyr U, Fetzer U, Steinbrückner C (1959) Versuche mit isonitrilen. Angew Chem 71:386–388Google Scholar
  5. 5.
    Hulme C, Gore V (2003) Multi-component reactions: emerging chemistry in drug discovery ‘from xylocain to crixivan’. Curr Med Chem 10:51–80CrossRefPubMedGoogle Scholar
  6. 6.
    Bodor N, Buchwald P (2000) Soft drug design: general principles and recent applications. Med Res Rev 20:58–101CrossRefPubMedGoogle Scholar
  7. 7.
    Leffingwell JC (2009) Cooling ingredient and their mechanism of action. In: Barel AO, Paye M, Maibach HI (eds) Handbook of cosmetic science and technology, Chapter 65. Informa Healthcare, New YorkGoogle Scholar
  8. 8.
    Welschoff N, Waldvogel SR (2010) Practical synthesis of optically pure menthylamines starting from racemic neomenthol. Synthesis 21:3596–3601; (1R,2S,5R)-2-isopropyl-5-methylcyclohexan-1-amine was synthesized according to the procedure reported by Welschoff et alGoogle Scholar
  9. 9.
    Dömling A, Ugi I (2000) Multicomponent reactions with isocyanides. Angew Chem Int Ed 39:3168–3210CrossRefGoogle Scholar
  10. 10.
    Dömling A (2006) Recent developments in isocyanide based multicomponent reactions in applied chemistry. Chem Rev 106:17–89CrossRefPubMedGoogle Scholar
  11. 11.
    Ruijter E, Orru RV (2013) Multicomponent reactions - opportunities for the pharmaceutical industry. Drug Discov Today Technol 10:15–20CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Tracey Pirali
    • 1
  • Ubaldina Galli
    • 1
  • Marta Serafini
    • 1
  • Alessia Griglio
    • 1
  • Armando A. Genazzani
    • 1
  • Gian Cesare Tron
    • 1
    Email author
  1. 1.Dipartimento di Scienze del FarmacoUniversità del Piemonte OrientaleNovaraItaly

Personalised recommendations