Muscarinic receptors affinity profiles

Mutschler, E. Affinity profiles of hexahydro-sila-difenidol analogues at muscarinic receptor subtypes. 

Receptor affinities of metabolites may variably contribute to the in-vivo or clinical action. For example, the olanzapine metabolite 2-hydroxmethyl-olanzapine has affinity to histamine Hj and adrenergic alpha-1 receptors comparable to that of the parent compound [58]. Further, N-desmethylclozapine, the main metabolite of clozapine, has remarkable agonism at muscarinic Mj receptors [59], and it is hypothesized that this action may greatly contribute to the uniquely beneficial clinical profile of clozapine [60]. 

Figure 3. Structures and affinity profiles (pA2 values) of (R)- and (S)-enantiomers of compounds 1 - 6 at muscarinic M] (r bit vas deferens), M2 (guinea-pig atria) and M3 receptors (guinea-pig ileum) center of chirality.

In contrast to tripitramine, spirotramine displayed, among muscarinic receptor subtypes investigated, the highest affinity towards the Mj subtype with a TpK value of 7.88 which was comparable to that observed for pirenzepine (piT , 8.19). Furthermore, spirotramine possesses a unique binding profile since it is able to discriminate, unlike tripitramine and pirenzepine, between Mi and M4 muscarinic receptors as well as among all other muscarinic receptor subtypes investigated as revealed by the selectivity ratio values (M1/M2, 48 M1/M3, 117 ... 

Angeli, P., Gualtieri, F, Maggie, R., Paparelli, F., Scapecchi, S., 1993. Affinity profiles at five cloned human muscarinic receptors (ml-m5) of a new series of antimuscarinic drugs, Pharm. Pharmacol. Lett. 3, 84-87. 

Beyond their action upon SERT and NET, venlafaxine (1), milnacipran (2) and duloxetine (3) are remarkably selective molecules. All three of them have displayed very low in vitro affinity Ki > 3(X)0 nM) for ai- and a2-adrenergic, histamine Hj, muscarinic, and DA D2 receptors, consistent with favorable side-effect profiles. Venlafaxine (1) and duloxetine (3) also have low affinity for a number of serotonergic receptors, and do not inhibit monoamine oxidase A or B. An expanded in vitro receptor profile of >50 receptors and binding sites... 

AF-DX-116 is an analog of pirenzepinethat differs markedly in its profile of muscarinic activities (102,103). It has greatest affinity for cardiac M2 receptors. Its cardioselectivity is dso observed in humans and may become useful in sinus bradycardia and AV block of vagal origin. 

Another compound structurally related to this series is the aminoethyl analogue of (R)-HHD, i.e. the (R)-enantiomer of the antiparkinsonian drug trihexyphenidyl (7, THP). (R)-TID proved to be an Mj-selective muscarinic antagonist with intermediate afiMty at M3 and at M4 and low affinity at M2 receptors. However, its stereoselectivity profile (R/S) of Mj=M3=M4> M2 is ver similar to that of HHD (Figure 4) [39]. 

Milnacipran selectively inhibits the reuptake of 5-HT (selectivity ratio, 9) at the presynaptic membrane site, thus increasing the concentration of 5-HT in the synaptic cleft (69). Although milnacipran is not a TCA, its mechanism of action is similar to that of imipramine, and its binding and reuptake inhibition profile more closely resembles that of the TCAs. Milnacipran has weak affinity for adrenergic, muscarinic, and Hi receptors and, therefore, is expected to be devoid of the prominent side effects observed for the TCAs. In clinical studies, milnacipran showed antidepressant efficacy similar to that of TCAs and SSRIs. 

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