Name: Besipirdine HCl
Synonyms: HP 749
Therapy Type: Small Molecule
Target Type: Other Neurotransmitter Systems
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: Aventis Pharmaceuticals, Inc. (was Hoechst)
Besipirdine was designed to address two biochemical deficits commonly observed in the AD brain: cholinergic and adrenergic activity. This drug has been shown to enhance the activity of both systems (Klein et al., 1996). Hypoactivity of the cholinergic system is a well-known characteristic of the AD brain. Similarly, AD is associated with loss of locus coeruleus neurons, degeneration of noradrenergic projections, and a decrease in cortical norepinephrine levels (Heneka et al., 2002; Bondareff et al., 1982).
Besipirdine hydrochloride, an indole-substituted analog of 4-aminopyridine, enhances both cholinergic and adrenergic neurotransmission in the central nervous system. It has been shown to have a high affinity for α2-adrenergic receptors (much lower affinity for α1-adrenergic receptors) and also to modulate cholinergic neurotransmission through unspecified mechanisms (Klein et al., 1996).
- Klein JT, Davis L, Olsen GE, Wong GS, Huger FP, Smith CP, Petko WW, Cornfeldt M, Wilker JC, Blitzer RD, Landau E, Haroutunian V, Martin LL, Effland RC. Synthesis and structure-activity relationships of N-propyl-N-(4-pyridinyl)-1H-indol-1-amine (besipirdine) and related analogs as potential therapeutic agents for Alzheimer's disease. J Med Chem. 1996 Jan 19;39(2):570-81. PubMed.
- Heneka MT, Galea E, Gavriluyk V, Dumitrescu-Ozimek L, Daeschner J, O'Banion MK, Weinberg G, Klockgether T, Feinstein DL. Noradrenergic depletion potentiates beta -amyloid-induced cortical inflammation: implications for Alzheimer's disease. J Neurosci. 2002 Apr 1;22(7):2434-42. PubMed.
- Bondareff W, Mountjoy CQ, Roth M. Loss of neurons of origin of the adrenergic projection to cerebral cortex (nucleus locus ceruleus) in senile dementia. Neurology. 1982 Feb;32(2):164-8. PubMed.
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