Dual-acting drugs: an in vitro study of nonimidazole histamine H3 receptor antagonists combining anticholinesterase activity.
Dual-acting compounds that combine H(3) antagonism with anticholinesterase properties are currently emerging as a novel and promising therapeutic approach in the treatment of multifactorial disorders primarily characterized by cholinergic deficits such as Alzheimer's disease. A series of novel nonimidazole H(3) ligands was developed from the chemical manipulation of 1,1'-octa-, -nona-, and -decamethylene-bis-piperidines--H(3) antagonists that had been the subject of previous investigations. These compounds were evaluated for in vitro binding affinity, antagonistic potency, and selectivity at rodent and human histamine H(3) receptors, inhibitory activity at rat brain cholinesterase, and in vivo CNS access and cholinomimetic effects. Within the present series, the tetrahydroaminoacridine hybrid 18 stands out as one of the most attractive molecules, synergistically combining nanomolar and selective H(3) antagonism with remarkable anticholinesterase activity. From this original starting point, it is hoped that future investigations will lead to dual-acting compounds that can selectively enhance central cholinergic neurotransmission and thus facilitate the treatment of cognitive disorders.
Dipartimento Farmaceutico, Università degli Studi di Parma, Vle GP Usberti 27A, 43100 Parma, Italy. matteo.incerti@unipr.it
Matteo
M
Incerti
Lisa
L
Flammini
Francesca
F
Saccani
Giovanni
G
Morini
Mara
M
Comini
Massimo
M
Coruzzi
Elisabetta
E
Barocelli
Vigilio
V
Ballabeni
Simona
S
Bertoni
D000818:Animals; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006168:Guinea Pigs; D054828:Histamine H3 Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D018100:Receptors, Histamine H3 / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
D002800:Cholinesterase Inhibitors; D054828:Histamine H3 Antagonists; D010880:Piperidines; D018100:Receptors, Histamine H3; C032727:piperidine