Hybridized and isosteric analogues of N1-acetyl-N4-dimethyl-piperazinium iodide (ADMP) and N1-phenyl-N4-dimethyl-piperazinium iodide (DMPP) with central nicotinic action.
A series of piperazine derivatives, obtained by hybridization of N1-acetyl-N4-dimethyl-piperazinium iodide (1, ADMP) and N1-phenyl-N4-dimethyl-piperazinium iodide (3, DMPP) or of the corresponding tertiary bases (2, 4) with arecoline (5) and arecolone (6) or by isosteric substitution of the phenyl ring of DMPP, has been synthesized. Hybridization afforded compounds that, both as tertiary bases and as iodomethylates, have no affinity for the nicotinic receptor. On the contrary, isosteric substitution gave compounds that maintain affinity for the receptor; among them, two tertiary bases (37, 38), show affinity in the nanomolar range for the nicotinic receptor. The pharmacological profile of these isomeric compounds is quite interesting as they present differences in their peripheral and central effects, suggesting that they interact with different subtypes of the nicotinic receptor.
Manetti
D
D
Dipartimento di Scienze Farmaceutiche, Università di Firenze, Italy.
Bartolini
A
A
Borea
P A
PA
Bellucci
C
C
Dei
S
S
Ghelardini
C
C
Gualtieri
F
F
Romanelli
M N
MN
Scapecchi
S
S
Teodori
E
E
Varani
K
K
D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004246:Dimethylphenylpiperazinium Iodide / Q000737:chemistry / Q000494:pharmacology*; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D007536:Isomerism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D000644:Quaternary Ammonium Compounds / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D013055:Spectrophotometry, Infrared
D000700:Analgesics; D010879:Piperazines; D000644:Quaternary Ammonium Compounds; D011978:Receptors, Nicotinic; D004246:Dimethylphenylpiperazinium Iodide; C080419:1,1-dimethyl-4-acetylpiperazinium