SAR studies on the potent and selective muscarinic antagonist 2-ethylthio-2,2-diphenylacetic acid N,N-diethylaminoethyl ester.

Molecular modification of the potent and selective muscarinic antagonist 2-ethylthio-2,2-diphenylacetic acid N,N-diethylaminoethyl ester was performed in order to identify M2 selective antagonists able to cross the blood brain barrier and potentially useful in the treatment of Alzheimer's disease. Modifications included substitution or hydrogenation of one of the phenyl rings as well as their incorporation in a tricyclic system. In general the changes introduced were detrimental for both affinity and selectivity. Only a modest M2 selectivity is present in some compounds that, on the other hand, carry a quaternary ammonium group which precludes their penetration into the brain.

Synthesis and alpha-adrenoreceptor blocking properties of phenoxybenzamine-related (2-chloroethyl)-(2,3-dihydrobenzo[1,4]dioxin- 2-ylmethyl)-(2-phenoxyethyl) amines.

A series of beta-chloroethylamines, structural hybrids of WB 4101, a competitive alpha 1-adrenoreceptor antagonist, and phenoxybenzamine, an irreversible alpha-adrenoreceptor antagonist, has been synthesized and tested in isolated rat vas deferens alpha-adrenoreceptors. Although, for all compounds, apparent blocking potency and alpha 1-selectivity are quite similar to those of phenoxybenzamine, affinity values calculated by taking into account the actual concentration of aziridinium ion in solution, reveal that compounds bearing a 1,4-benzodioxan-2-ylmethyl moiety, display a significantly higher potency for both alpha 1- and alpha 2-adrenoreceptors than compounds having a benzyl group. In addition, two of the compounds, having both methyl and methoxy groups in their structure, show a marked discontinuity in the alpha 1-adrenoreceptor concentration-inhibition curve, with a plateau in the range 30-100 nM. Stereochemical aspects are also shown to play an important role in the binding. The biological results suggest that the two irreversible antagonists may be able to discriminate between two alpha 1-adrenoreceptor subtypes, which are both involved in the noradrenaline-induced contraction of the epididymal portion of rat vas deferens.

Dialkylaminoalkyl esters of 2,2-diphenyl-2-alkylthioacetic acids: a new class of potent and functionally selective muscarinic antagonists.

The synthesis and pharmacological activity as muscarinic antagonists of a number of 2-alkylthio-2,2-diphenylacetic acid esters are reported. The compounds studied are potent muscarinic antagonists and many of them show from moderate to high selectivity toward M2 or toward M1 and M2 receptors when tested on tissues but lack selectivity on five muscarinic human receptors (m1-m5) cloned and expressed in CHO-K1 cells. As a consequence, the compounds behave as functionally selective antagonists. Those showing M2 selectivity appear to be good drug candidates for the treatment of cognitive disorders connected with central cholinergic deficit.

Synthesis and muscarinic receptors affinity of a series of antagonist bivalent ligands.

A series of bivalent ligands (2-8) derived from 2,2-diphenyl-[1,3]-dioxolan-4-ylmethyl-dimethylamine methiodide 1 has been synthesized and tested to evaluate affinity and selectivity for M1, M2 and M3 muscarinic receptor subtypes. In order to study the contribution of the spacer and of a second cationic head to the binding process, unsymmetrical ligands (9,10) have also been prepared. The results, expressed in terms of pA2 values, show that, although the spacer negatively affects the interaction of the bivalent ligands with the three receptor subtypes, affinity and selectivity are modulated by its length; this indicates that the pharmacophore binding sites are organized differently with respect to their mutual proximity and orientation, in each receptor subtype.