Versatile Picklocks To Access All Opioid Receptors: Tuning the Selectivity and Functional Profile of the Cyclotetrapeptide c[Phe-d-Pro-Phe-Trp] (CJ-15,208).
Recently, the tryptophan-containing noncationizable opioid peptides emerged with atypical structure and unexpected in vivo activity. Herein, we describe analogs of the naturally occurring mixed κ/μ-ligand c[Phe-d-Pro-Phe-Trp] 1 (CJ-15,208). Receptor affinity, selectivity, and agonism/antagonism varied upon enlarging macrocycle size, giving the μ-agonist 9 or the δ-antagonist 10 characterized by low nanomolar affinity. In particular, the μ-agonist c[β-Ala-d-Pro-Phe-Trp] 9 was shown to elicit potent antinociception in a mouse model of visceral pain upon systemic administration.
Department of Chemistry "G. Ciamician", University of Bologna , Via Selmi 2, 40126 Bologna, Italy.
Rossella
R
De Marco
Department of Pharmacy and Biotechnology, University of Bologna , Via Irnerio 48, 40126 Bologna, Italy.
Andrea
A
Bedini
Department of Pharmacy and Biotechnology, University of Bologna , Via Irnerio 48, 40126 Bologna, Italy.
Santi
S
Spampinato
Department of Chemistry "G. Ciamician", University of Bologna , Via Selmi 2, 40126 Bologna, Italy.
Lorenzo
L
Cavina
Department of Chemistry "G. Ciamician", University of Bologna , Via Selmi 2, 40126 Bologna, Italy.
Edoardo
E
Pirazzoli
Department of Chemistry "G. Ciamician", University of Bologna , Via Selmi 2, 40126 Bologna, Italy.
Luca
L
Gentilucci
D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D009292:Narcotic Antagonists / Q000737:chemistry / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011957:Receptors, Opioid / Q000819:agonists* / Q000378:metabolism; D059265:Visceral Pain / Q000188:drug therapy
D000700:Analgesics; C540936:CJ 15,208; D009292:Narcotic Antagonists; D010456:Peptides, Cyclic; D011957:Receptors, Opioid