From pyrrolidinyl-benzodioxane to pyrrolidinyl-pyridodioxanes, or from unselective antagonism to selective partial agonism at α4β2 nicotinic acetylcholine receptor.
Each of the four aromatic -CH= of (S,R)-2-pyrrolidinyl-1,4-benzodioxane [(S,R)-6] and of its epimer at the dioxane stereocenter (S,S)-6, previously reported as α4β2 nAChR ligands, was replaced with nitrogen. The resulting four diastereoisomeric pairs of pyrrolidinyl-pyridodioxanes were studied for the nicotinic affinity and activity at α4β2, α3β4 and α7 nAChR subtypes and compared to their common carbaisostere. It turned out that such isosteric substitutions are highly detrimental, but with the important exception of the S,R stereoisomer of the pyrrolidinyl-pyridodioxane with the pyridine nitrogen adjacent to the dioxane and seven atoms distant from the pyrrolidine nitrogen. Indeed, this stereo/regioisomer not only maintained the α4β2 affinity of [(S,R)-6], but also greatly improved in selectivity over the α3β4 and α7 subtypes and, most importantly, exhibited a highly selective α4β2 partial agonism. The finding that [(S,R)-6] is, instead, an unselective α4β2 antagonist indicates that the benzodioxane substructure confers affinity for the α4β2 nAChR binding site, but activation of this receptor subtype needs benzodioxane functionalization under strict steric requirements, such as the previously reported 7-OH substitution or the present isosteric modification.
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
CNR, Istituto di Neuroscienze, and Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, via Vanvitelli 32, Milano, I-20129, Italy.
Cecilia
C
Gotti
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, via Mangiagalli 25, I-20133, Milano, Italy.
Laura
L
Fumagalli
CNR, Istituto di Neuroscienze, and Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, via Vanvitelli 32, Milano, I-20129, Italy.
Francesca
F
Fasoli
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, via Mangiagalli 25, I-20133, Milano, Italy.
Matteo
M
Binda
CNR, Istituto di Neuroscienze, and Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, via Vanvitelli 32, Milano, I-20129, Italy.
Vanessa
V
Mucchietto
I.R.C.C.S. Neuromed, Istituto Neurologico Mediterraneo, via Atinese 18, I-86077, Pozzilli (Isernia), Italy.
Miriam
M
Sciaccaluga
Dipartimento di Fisiologia e Farmacologia, Università di Roma La Sapienza, Piazzale Moro 5, 00185 Roma, Italy.
Simona
S
Plutino
I.R.C.C.S. Neuromed, Istituto Neurologico Mediterraneo, via Atinese 18, I-86077, Pozzilli (Isernia), Italy; Dipartimento di Fisiologia e Farmacologia, Università di Roma La Sapienza, Piazzale Moro 5, 00185 Roma, Italy.
Sergio
S
Fucile
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
D001555:Benzene Derivatives / Q000737:chemistry / Q000494:pharmacology; D004146:Dioxanes / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D018722:Nicotinic Agonists / Q000737:chemistry* / Q000494:pharmacology*; D011759:Pyrrolidines / Q000737:chemistry* / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013329:Structure-Activity Relationship
D001555:Benzene Derivatives; D004146:Dioxanes; D018722:Nicotinic Agonists; D011759:Pyrrolidines; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2
Antagonism; Benzodioxane; Partial agonism; Pyridodioxane; α3β4 nAChR; α4β2 nAChR