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Tesi etd-02122020-171955


Thesis type
Tesi di dottorato di ricerca
Author
MEINI, SERENA
URN
etd-02122020-171955
Title
Synthesis and biological evaluation of novel cannabinoid receptors allosteric modulators
Settore scientifico disciplinare
CHIM/08
Corso di studi
SCIENZA DEL FARMACO E DELLE SOSTANZE BIOATTIVE
Supervisors
tutor Dott. Bertini, Simone
Parole chiave
  • cannabinoid allosteric synthesis CB1 CB2
Data inizio appello
10/03/2020;
Consultabilità
Parziale
Data di rilascio
10/03/2023
Riassunto analitico
The endocannabinoid system (ECS) is a complex biochemical system, ubiquitously distributed in the organism
and constituted by specific receptors, (CB1R and CB2R), endogenous ligands (i.e. endocannabinoids) and all
the enzymes responsible for their synthesis, transport and degradation. ECS is considered a promising
therapeutic target for the treatment of several diseases, due to its involvement in different biochemical
processes such as metabolism and energy balance, pain transmission and inflammation, neurodegeneration
and many others. In spite of the development of a wide number of cannabinoid receptors orthosteric ligands,
this class of compounds has a very limited use in therapy, because of the elicitation of severe side effects, like
psychotropic effects, cognitive impairments, mood alterations and suicidal tendencies. In comparison with the
use of cannabinoid receptors orthosteric ligands, allosteric modulation is related to several pharmacological
benefits such as a “fine tuning” of the signaling, saturability of the effect and an increased subtype selectivity.
Given these premises, which label allosteric modulation as a potential safer therapeutic approach, in this thesis
I reported the design, synthesis and biological evaluation of new compounds, with the aim to deepen the
knowledge of the structural requirements of CBRs allosteric binding sites and to identify novel cannabinoid
receptors modulators with higher potency and subtype selectivity. My thesis manuscript describes two
different topics:
- Design, synthesis and pharmacological evaluation of CB1R selective allosteric modulators with diaryl
urea structure. Starting from the well-known CB1R selective allosteric modulator PSNCBAM-1, I
designed, synthesized and biologically evaluated new derivatives, obtained combining the most recent
promising structural features reported in literature.
- Design, synthesis and pharmacological evaluation of CB2R selective allosteric modulators with
pyridine-2-one structure. Starting from the first synthetic CB2R selective allosteric modulator C2, I
designed, synthesized and biologically evaluated five different series of derivatives, differently
modifying the substituents of the central core.
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