Albert Badia

Pyrano(3,2-c)quinoline-6-Chlorotacrine Hybrids as a Novel Family of Acetylcholinesterase- and β-Amyloid-Directed Anti-Alzheimer Compounds

Two isomeric series of dual binding site acetylcholinesterase (AChE) inhibitors have been designed, synthesized, and tested for their ability to inhibit AChE, butyrylcholinesterase, AChE-induced and self-induced beta-amyloid (Abeta) aggregation, and beta-secretase (BACE-1) and to cross blood-brain barrier. The new hybrids consist of a unit of 6-chlorotacrine and a multicomponent reaction-derived pyrano[3,2-c]quinoline scaffold as the active-site and peripheral-site interacting moieties, respectively, connected through an oligomethylene linker containing an amido group at variable position. Indeed, molecular modeling and kinetic studies have confirmed the dual site binding of these compounds. The new hybrids, and particularly 27, retain the potent and selective human AChE inhibitory activity of the parent 6-chlorotacrine while exhibiting a significant in vitro inhibitory activity toward the AChE-induced and self-induced Abeta aggregation and toward BACE-1, as well as ability to enter the central nervous system, which makes them promising anti-Alzheimer lead compounds.

Assessing the (a)symmetry of concentration-effect curves: empirical versus mechanistic models

Modeling the shape of concentration-effect curves is of prime importance in pharmacology. Geometric descriptors characterizing these curves (the upper and lower asymptotes, the mid-point, the mid-point slope, and the point of inflection) are used for drug comparison or for assessing the change in agonist function after a system modification. The symmetry or asymmetry around the mid-point of a concentration-effect curve is a fundamental property that, regretfully, is often overlooked because, generally, models yielding exclusively symmetric curves are used. In the present review, empirical and mechanistic models are examined in their ability to fit experimental data. The geometric parameters of a survey of empirical models, the Hill equation, a logistic variant that we call the modified Hill equation, the Richards function, and the Gompertz model are determined. To analyze the relationship between asymmetry and mechanism, some examples from the ionic channel field, in an increasing degree of complexity, are used. It is shown that asymmetry arises from ionic channels with multiple binding sites that are partly occupied. The operational model of agonism is discussed both in its empirical general formulation and including the signal transduction mechanisms through G-protein-coupled receptors. It is shown that asymmetry results from systems where receptor distribution is allowed. Developed mathematical models are compared for describing experimental data on alpha-adrenoceptors. The existence or not of a relationship between the shape of the curves and receptor reserve is discussed.

Synthesis and evaluation of tacrine–Huperzine a hybrids as acetylcholinesterase inhibitors of potential interest for the treatment of alzheimer’s disease

Seventeen polycyclic compounds related to tacrine and huperzine A have been prepared as racemic mixtures and tested as acetylcholinesterase (AChE) inhibitors. The conjunctive pharmacomodulation of huperzine A (carbobicyclic substructure) and tacrine (4-aminoquinoline substructure) led to compound 7jy, 2.5 times less active than tacrine as AChE inhibitor, but much more active than its (Z)-stereoisomer (7iy). Derivatives 7dy and 7ey, lacking the ethylidene substituent, showed to be more active than tacrine. Many other structural modifications of 7jy led to less active compounds. Compounds 7dy and 7ey also showed to be much more active than tacrine in reversing the partial neuromuscular blockade induced by d-tubocurarine.

N-Benzylpiperidine derivatives of 1,2,4-thiadiazolidinone as new acetylcholinesterase inhibitors

A new family of 1,2,4-thiadiazolidinone derivatives containing the N-benzylpiperidine fragment has been synthesised. The acetylcholinesterase (AChE) inhibitory activity of all compounds was measured using Ellmans method and some of them turned out to be as potent as tacrine. Furthermore, compound 13 was as active as tacrine in reversing the blockade induced by tubocurarine at rat neuromuscular junction. Additionally, receptor binding studies provided new lead compounds for further development of alpha2-adrenergic and sigma-receptor antagonists. Molecular dynamic simulation using X-ray crystal structure of AChE from Torpedo californica was used to explain the possible binding mode of these new compounds.

Synthesis and acetylcholinesterase/butyrylcholinesterase inhibition activity of new tacrine-like analogues

The synthesis and preliminary results for acetylcholinesterase and butyrylcholinesterase inhibition activity of a series of pyrano[2,3-b]quinolines (2, 3) and benzonaphthyridines (5, 6) derivatives are described. These molecules are tacrine-like analogues which have been prepared from readily available polyfunctionalized ethyl [6-amino-5-cyano-4H-pyrans and 6-amino-5-cyanopyridines]-3-carboxylates via Friedlander condensation with selected ketones. These compounds showed moderate acetylcholinesterase inhibition activity, the more potent (2e, 5b) being 6 times less active than tacrine. The butyrylcholinesterase activity of some of these molecules is also discussed.

Huprine–Tacrine Heterodimers as Anti-Amyloidogenic Compounds of Potential Interest against Alzheimer’s and Prion Diseases

A family of huprine-tacrine heterodimers has been developed to simultaneously block the active and peripheral sites of acetylcholinesterase (AChE). Their dual site binding for AChE, supported by kinetic and molecular modeling studies, results in a highly potent inhibition of the catalytic activity of human AChE and, more importantly, in the in vitro neutralization of the pathological chaperoning effect of AChE toward the aggregation of both the β-amyloid peptide (Aβ) and a prion peptide with a key role in the aggregation of the prion protein. Huprine-tacrine heterodimers take on added value in that they display a potent in vitro inhibitory activity toward human butyrylcholinesterase, self-induced Aβ aggregation, and β-secretase. Finally, they are able to cross the blood-brain barrier, as predicted in an artificial membrane model assay and demonstrated in ex vivo experiments with OF1 mice, reaching their multiple biological targets in the central nervous system. Overall, these compounds are promising lead compounds for the treatment of Alzheimers and prion diseases.

Tacrine-based dual binding site acetylcholinesterase inhibitors as potential disease-modifying anti-Alzheimer drug candidates.

Two novel families of dual binding site acetylcholinesterase (AChE) inhibitors have been developed, consisting of a tacrine or 6-chlorotacrine unit as the active site interacting moiety, either the 5,6-dimethoxy-2-[(4-piperidinyl)methyl]-1-indanone fragment of donepezil (or the indane derivative thereof) or a 5-phenylpyrano[3,2-c]quinoline system, reminiscent to the tryciclic core of propidium, as the peripheral site interacting unit, and a linker of suitable length as to allow the simultaneous binding at both sites. These hybrid compounds are all potent and selective inhibitors of human AChE, and more interestingly, are able to interfere in vitro both formation and aggregation of the beta-amyloid peptide, the latter effects endowing these compounds with the potential to modify Alzheimers disease progression.

Novel huprine derivatives with inhibitory activity toward β-amyloid aggregation and formation as disease-modifying anti-Alzheimer drug candidates.

A new family of dual binding site acetylcholinesterase (AChE) inhibitors has been designed, synthesized, and tested for their ability to inhibit AChE, butyrylcholinesterase (BChE), AChE‐induced and self‐induced β‐amyloid (Aβ) aggregation and β‐secretase (BACE‐1), and to cross the blood–brain barrier. The new heterodimers consist of a unit of racemic or enantiopure huprine Y or X and a donepezil‐related 5,6‐dimethoxy‐2‐[(4‐piperidinyl)methyl]indane moiety as the active site and peripheral site to mid‐gorge‐interacting moieties, respectively, connected through a short oligomethylene linker. Molecular dynamics simulations and kinetics studies support the dual site binding to AChE. The new heterodimers are potent inhibitors of human AChE and moderately potent inhibitors of human BChE, AChE‐induced and self‐induced Aβ aggregation, and BACE‐1, and are predicted to be able to enter the central nervous system (CNS), thus constituting promising multitarget anti‐Alzheimer drug candidates with the potential to modify the natural course of this disease.

Mechanisms underlying the differential sensitivity to a1-adrenoceptor activation in the bisected rat vas deferens

1 The factors underlying the different responsiveness of the prostatic and epididymal portions of rat vas deferens to α1‐adrenoceptor stimulation were investigated. 2 The α1‐adrenoceptors in membranes of both halves of rat vas deferens were labelled with [3H]‐prazosin and the affinities of agonists and antagonists for these receptors were determined. In saturation studies, the Bmax and KD values for [3H]‐prazosin in membranes of both portions were the same. 3 In competition studies, the inhibition curves for phentolamine were biphasic and consistent with the presence of both α1a‐ and α1b‐adrenoceptor subtypes. The proportions of binding sites with high and low affinity for phentolamine in both halves of rat vas deferens were similar and in good agreement with the percentages of binding sites for WB‐4101 and phentolamine previously reported in the whole rat vas deferens. 4 The phenylethylamines displaced [3H]‐prazosin with a shallow inhibition curve. The data are compatible with the assumption of two affinity states for the binding sites. For the imidazoline compounds no such distinct affinity states could be demonstrated. 5 The affinity for, and the relative intrinsic efficacy on postsynaptic α1‐adrenoceptors of both portions of rat vas deferens were studied for noradrenaline, phenylephrine and methoxamine by irreversible inactivation of the α1‐adrenoceptors by phenoxybenzamine. The parameters for partial agonists were determined by comparing the responses to the partial agonist to those of a full agonist in the same tissue. Homogeneous estimates of the equilibrium dissociation constants (Ka) were obtained, indicating that these agonists bind to the receptors of both tissues in an identical manner. Further, estimation of the intrinsic efficacy of agonists relative to noradrenaline, indicated no differences between the two halves of rat vas deferens. 6 Ka values for agonist activation of the functional α1‐adrenoceptors were compared with KI values for agonist inhibition of specific [3H]‐prazosin binding. The Ka values were well correlated with the low affinity KI values for phenylethylamines in both portions of rat vas deferens, suggesting that the initial event in signal transduction by α1‐adrenoceptors is the binding to the low affinity state of the receptor. 7 There was a non‐linear relationship between response and receptor occupancy in both halves of rat vas deferens but the occupancy‐response coupling was more efficient in the epididymal than in the prostatic portion. This fact may account for the differences observed in the functional responses.

Synthesis and evaluation of tacrine-related compounds for the treatment of Alzheimer's disease

Abstract A number of polycyclic compounds related to tacrine have been prepared by condensation of ortho-aminobenzonitriles and 2-aminocyclopentenecarbonitrile with several C2v-symmetric diketones under AlCl3 or ZnCl2 catalysis. Monocondensation products 8 together with syn- and anti-dicondensation products 9 and 10, respectively, were formed in different proportions depending mainly on the starting diketone. These compounds were separated by column chromatography, fully characterized by spectroscopic and elemental analyses and tested as acetylcholinesterase (AchE) inhibitors. Syn- and anti-compounds 9 and 10, derived from diketones 7y and 7z, have significant anti-AchE activity although compounds 8 and derivatives of diketones 7v, 7w and 7x were inactive in the range of concentrations studied. Compound 9ay was the most potent of the group, being 4.4-fold less active than tacrine as anti-AchE in biochemical assays, but only slightly less potent in biological studies and 3-fold less toxic. Compound 9ay was also able to reverse cognitive deficits in middle-aged rats.