Rigid analogs of DMPP as probes for the nicotinic receptors.
Chemical manipulation of the nicotinic agonist DMPP, endowed with modest activity on the central receptors, definitely improved its affinity and pharmacokinetic properties. Although their pharmacophore is somehow different from that of classical nicotinic ligands, some DMPP derivatives show low nanomolar affinity for the central nicotinic receptors. Introduction of rigidity in the structure of DMPP and in that of its analogue 1-(3-pyridyl)piperazine, resulted in molecules with lower or null affinity for the central nicotinic receptors. This suggests that the frozen structures chosen either do not represent the bioactive conformation, or their volume is not compatible with the space available within the interaction site.
Guandalini
Luca
L
Dipartimento di Scienze Farmaceutiche, Università di Firenze, via Ugo Schiff 6, 50019 Sesto Fiorentino (FI), Italy.
Martini
Elisabetta
E
Martelli
Cecilia
C
Romanelli
M Novella
MN
Varani
Katia
K
D000818:Animals; D001665:Binding Sites; D004246:Dimethylphenylpiperazinium Iodide / Q000138:chemical synthesis / Q000494:pharmacology*; D015195:Drug Design; D008024:Ligands; D015394:Molecular Structure; D018722:Nicotinic Agonists / Q000138:chemical synthesis / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship
D008024:Ligands; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D004246:Dimethylphenylpiperazinium Iodide