Novel 5-substituted 3-hydroxyphenyl and 3-nitrophenyl ethers of S-prolinol as α4β2-nicotinic acetylcholine receptor ligands.
A series of 3-nitrophenyl and 3-hydroxyphenyl ethers of (S)-N-methylprolinol bearing bulky and lipophilic substituents at phenyl C5 were tested for affinity at α4β2 and α3β4 nAChRs. The two phenyl ethers 5-substituted with 6-hydroxy-1-hexynyl showed high α4β2 affinity and significantly increased α4β2/α3β4 selectivity compared to the respective unsubstituted parent compounds. Within the two series of novel phenyl ethers, we observed parallel shifts in affinity and, furthermore, the increase in α4β2/α3β4 selectivity resulting from the hydroxyalkynyl substitution parallels that reported for the same modification at the 3-pyridyl ether of (S)-N-methylprolinol (A-84543), a well-known potent α4β2 agonist. On the basis of these results, our nitrophenyl and hydroxyphenyl prolinol ethers can be considered bioisosteres of the pyridyl ether A-84543 and lead compounds candidable to analogous optimization processes.
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, via Mangiagalli 25, I-20133 Milano, Italy.
Cristiano
C
Bolchi
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, via Mangiagalli 25, I-20133 Milano, Italy.
Francesco
F
Bavo
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, via Mangiagalli 25, I-20133 Milano, Italy.
Laura
L
Fumagalli
CNR, Istituto di Neuroscienze, Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, via Vanvitelli 32, I-20129 Milano, Italy.
Cecilia
C
Gotti
CNR, Istituto di Neuroscienze, Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, via Vanvitelli 32, I-20129 Milano, Italy.
Francesca
F
Fasoli
CNR, Istituto di Neuroscienze, Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, via Vanvitelli 32, I-20129 Milano, Italy.
Milena
M
Moretti
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, via Mangiagalli 25, I-20133 Milano, Italy. Electronic address: marco.pallavicini@unimi.it.
Marco
M
Pallavicini
D000818:Animals; D006801:Humans; D008024:Ligands; D018722:Nicotinic Agonists / Q000737:chemistry* / Q000494:pharmacology*; D010647:Phenyl Ethers / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D011759:Pyrrolidines / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013329:Structure-Activity Relationship
C116733:3-(2-(pyrrolidinyl)methoxy)pyridine; D008024:Ligands; D018722:Nicotinic Agonists; D010647:Phenyl Ethers; D011725:Pyridines; D011759:Pyrrolidines; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; C010509:prolinol
6-Hydroxy-1-hexinyl; A-84543; Affinity; Bioisosterism; Ligand; nAChR