An LP1 analogue, selective MOR agonist with a peculiar pharmacological profile, used to scrutiny the ligand binding domain.
The hypothesis that central analgesia with reduced side effects is obtainable by occupying an 'allosteric' site in the MOR ligand binding domain requires the development of new ligands with peculiar pharmacological profile to be used as tools. New benzomorphan derivatives, analogues of LP1, a multitarget MOR agonist/DOR antagonist, were designed to examine in depth MOR ligand binding domain. Compound 5, bearing a diphenylic N-substituent on the benzomorphan nucleus, showed an affinity (Kiμ=0.5±0.2nM) comparable to that of LP1 and a better selectivity versus DOR and KOR. It elicits antinociceptive effects in ex vivo (GPI) and in vivo. This new compound engages receptor amino acidic residues not reached by LP1 and by other established MOR ligands. Molecular modeling studies, conducted on 5 and on several reference compounds, allowed us to propose possible residues in the MOR ligand binding domain essential for their interactions with 'orthosteric' and 'allosteric' binding sites.
Department of Drug Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy. Electronic address: s.ronsisvalle@unict.it.
Simone
S
Ronsisvalle
Department of Drug Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy.
Giuseppina
G
Aricò
Department of Drug Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy.
Federica
F
Panarello
Department of Drug Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy.
Angelo
A
Spadaro
Department of Drug Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy.
Lorella
L
Pasquinucci
Department of Drug Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy.
Maria S
MS
Pappalardo
Department of Drug Sciences, Pharmacology and Toxicology Section, University of Catania, Italy.
Carmela
C
Parenti
Department of Biomedical and Biotechnological Sciences, University of Catania, Italy.
Nicole
N
Ronsisvalle
D000818:Animals; D001575:Benzomorphans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D057809:HEK293 Cells; D006801:Humans; D007082:Ileum / Q000187:drug effects; D008024:Ligands; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D017450:Receptors, Opioid, mu / Q000819:agonists*; D013329:Structure-Activity Relationship
C569975:3-((2R,6R,11R)-8-hydroxy-6,11-dimethyl-1,4,5,6-tetrahydro-2,6-methano-3-benzazocin-3(2H)-yl)-N-phenylpropanamide; D001575:Benzomorphans; D008024:Ligands; D017450:Receptors, Opioid, mu
6,7-Benzomorphan scaffold; GPI and MVD assays; MOR agonists; Modeling studies; Radioligand competition-binding assay; Tail-flick test