Maria Laura Bolognesi

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Our understanding of the pathogenesis of diseases has advanced enormously in recent decades. As a consequence, drug discovery has gradually shifted from an entirely humanphenotype-based endeavor to today’s reductionist approach centered on single molecular targets. The focus has shifted from the early animal models to isolated proteins via cellular models.(More)
1. Experiments were carried out in human detrusor strips to characterize muscarinic receptor subtypes involved in the prejunctional regulation of acetylcholine (ACh) release from cholinergic nerve terminals, and in the postjunctional smooth muscle contractile response. 2. In detrusor strips preincubated with [3H]-choline, electrical field stimulation (600(More)
The binding selectivity of the muscarinic antagonist tripitramine has been tested on the five cloned human muscarinic receptor subtypes (Hm1 to Hm5) expressed in chinese hamster ovary (CHO-K1) cells. The results indicate that tripitramine binds to the muscarinic Hm2 receptor with a Ki value of 0.27 +/- 0.02 nM. Tripitramine distinguishes Hm2 vs. Hm4 by a(More)
In this work, we review and comment upon the challenges and the 'quo vadis' in Alzheimer's disease drug discovery at the beginning of the new millennium. We emphasize recent approaches that, moving on from a target-centric approach, have produced innovative molecular probes or drug candidates. In particular, the discovery of endosome-targeted BACE1(More)
Alzheimer's disease (AD) is a multifactorial syndrome with several target proteins contributing to its etiology. To confront AD, an innovative strategy is to design single chemical entities able to simultaneously modulate more than one target. Here, we present compounds that inhibit acetylcholinesterase and NMDA receptor activity. Furthermore, these(More)
Novel multi-target-directed ligands were designed by replacing the inner dipiperidino function of 3 with less flexible or completely rigid moieties to obtain compounds endowed with multiple biological properties that might be relevant to Alzheimer's disease. 15 was the most interesting, inhibiting AChE in the nanomolar range and inhibiting AChE-induced and(More)
The universal template approach to drug design foresees that a polyamine can be modified in such a way to recognize any neurotransmitter receptor. Thus, hybrids of polymethylene tetraamines and philanthotoxins, exemplified by methoctramine (1) and PhTX-343 (2), respectively, were synthesized to produce novel inhibitors of muscular nicotinic acetylcholine(More)
A library of 11 entries, featuring a 2,5-diamino-1,4-benzoquinones nucleus as spacer connecting two aromatic prion recognition motifs, was designed and evaluated against prion infection. Notably, 6-chloro-1,2,3,4-tetrahydroacridine 10 showed an EC(50) of 0.17 μM, which was lower than that displayed by reference compound BiCappa. More importantly, 10(More)
The concept that polyamines may represent a universal template in the receptor recognition process is embodied in the design of new selective muscarinic ligands. Tetraamines 4-7 and 16-20 and diamine diamides 8-15 were synthesized, and their pharmacological profiles at muscarinic receptor subtypes were assessed by functional experiments in isolated guinea(More)