Affinity and efficacy correlate with chemical structure more than potency does in a series of pentatomic cyclic muscarinic agonists

Angeli, Piero; Brasili, Livio; Giannella, Maddalena; Gualtieri, Fulvio; Pigini, Maria

doi:10.1111/j.1476-5381.1985.tb11076.x

Cited by 13 publications

(1 citation statement)

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“…According to Furchgott's theory, differences in −log K D of at least 0.5 are indicative of receptor heterogeneity; at the same time we know that the comparison of agonist potencies on different tissues is not sufficient to claim for receptor heterogeneity. , Consequently, further pharmacological parameters such as affinity and relative efficacy have been determined for the pair of enantiomers (+)- 5 and (−)- 5 (Table ).…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Pharmacological Characterization of Enantiomerically Pure Muscarinic Agonists: Difluoromuscarines

et al. 1997

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The four homochiral 4-deoxy-4,4-difluoromuscarine stereoisomers (difluoromuscarines) were prepared in very high enantiomeric excess. A convenient sequence based on the use of natural as well as "unnatural" ethyl lactate allowed the synthesis of target compounds, whose absolute configuration is dictated by that of the starting synthon. Quaternary ammonium salts (+)-5, (-)-5, (-)-6, and (+)-6 were tested in vitro on guinea pig tissues, and their muscarinic potency was evaluated at M2 (heart) and M3 (ileum and bladder) muscarinic receptor subtypes. The eutomer (+)-5 and distomer (-)-5 were also tested in vivo on pithed rat, and their muscarinic activity at the M1 receptor subtype was compared with those of racemic muscarine [(+/-)-1] and (2S,4R,5S)-4-deoxy-4-fluoromuscarine [(+)-4]. Further pharmacological parameters such as affinity, relative efficacy, and enantioselectivity have been determined for compounds (+)-5 and (-)-5 at M2 (heart force and rate) and M3 (ileum and bladder) receptors in order to investigate muscarinic receptor heterogeneity. The four homochiral difluoromuscarines behave as muscarinic agonists in all the tests with a potency trend which is different from that previously observed with the 4-deoxy-4-fluoromuscarines and (+/-)-1, thus indicating the intervention of the second fluorine atom on the receptor-ligand interaction. Moreover, the second fluorine atom produces significant differences in the affinity and relative efficacy values of compounds (+)-5 and (-)-5 at M2 and M3 subtypes, which could be attributed to a heterogeneity between the muscarinic receptors mediating heart rate and heart force and those involved in the contraction of ileum and bladder.

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Section: Resultsmentioning

confidence: 99%

Synthesis and Pharmacological Characterization of Enantiomerically Pure Muscarinic Agonists: Difluoromuscarines

et al. 1997

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Mechanisms of chiral recognition in xenobiotic metabolism and drug‐receptor interactions

Testa

1989

Chirality

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KEY WORDS: substrate enantioselectivity, product enantioselectivity, MichaelisMenten analysis, intrinsic activity, potency, receptor affinity, efficacy CONCEPTUAL STEPS IN THE INTERACTION OF XENOBIOTICS WITH BIOLOGICAL SYSTEMSChiral recognition is an essential component of pharmacological events, be they of a pharmacokinetic (e.g., xenobiotic metabolism) or pharmacodynamic nature (e.g., receptor-mediated effects). Thus, an in depth understanding of pharmacological events cannot dispense with the molecular mechanisms underlying chiral recognition. But at which step(s) of pharmacological events does chiral recognition occur? This is the question addressed here. A number of scientists have found answers in their respective fields, yet a unifying view is given here that may expand our perception of the fundamental similitude between pharmacodynamic and pharmacokinetic events?From a general viewpoint, the interaction of a xenobiotic, and more generally of any chemical compound, with a biological system can be broken down into three steps' : 1. A penetration step (measured as partition), involving entry of the compound into the compartment (cell, organelle, or membrane) of the acceptor, receptor, or enzyme.2. A recognition step (measured as affinity), involving the binding (complex formation) to the acceptor, receptor, or enzymatic site.3. An activation step (measured by potency, velocity, etc.), involving the molecular effect itself, e.g., activation or blockade of receptor, enzymatic reaction leading to metabolite formation.These three steps are conceptual ones, and, as such, have the utility and limitation of schematic perceptions. Also, situations exist that involve only two of the three steps. Thus, penetration is bypassed when working with isolated enzymes or macromolecules. Binding does not occur in nonenzymatic reactions, and there is no activation in "silent" interactions with various macromolecules and membranes. Yet, in spite of its simplificative character, this model appears useful in interpreting pharmacodynamics as well as pharmacokinetics events.In this short review, it is demonstrated that in pharmacological processes the binding and/or the activation step can contribute to chiral recognition. Note that the penetration step, which involves comparatively weak interactions with chiral macromolecular assemblies, should also contribute to the chiral recognition of bioactive agents. Lack of explicit data, however, precludes a fair assessment of the (presumably weak) contribution of 0 1989 Alan R. Liss, Inc. the penetration step, and the discussion to follow will be restricted to the binding and activation steps. XENOBIOTIC METABOLISMEnantioselectivity in xenobiotic metabolism can take two quite distinct forms, namely, substrate enantioselectivity and product enantioselectivity. The former involves the differential metabolism of two enantiomeric substrates under identical conditions, and it must be contrasted with product enantioselectivity and, more generally, with product stereoselectivity, which implies t...

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¹³C NMR spectra of 1,3‐oxathiolane, 1,3‐oxathiolane 3‐oxide and 1,3‐oxathiolane 3,3‐dioxide derivatives

Teodori

Melani

Gualtieri

1986

Journal of Heterocyclic Chem

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Affinity and efficacy correlate with chemical structure more than potency does in a series of pentatomic cyclic muscarinic agonists

Cited by 13 publications

References 9 publications

Synthesis and Pharmacological Characterization of Enantiomerically Pure Muscarinic Agonists: Difluoromuscarines

Synthesis and Pharmacological Characterization of Enantiomerically Pure Muscarinic Agonists: Difluoromuscarines

Mechanisms of chiral recognition in xenobiotic metabolism and drug‐receptor interactions

¹³C NMR spectra of 1,3‐oxathiolane, 1,3‐oxathiolane 3‐oxide and 1,3‐oxathiolane 3,3‐dioxide derivatives

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Affinity and efficacy correlate with chemical structure more than potency does in a series of pentatomic cyclic muscarinic agonists

Cited by 13 publications

References 9 publications

Synthesis and Pharmacological Characterization of Enantiomerically Pure Muscarinic Agonists: Difluoromuscarines

Synthesis and Pharmacological Characterization of Enantiomerically Pure Muscarinic Agonists: Difluoromuscarines

Mechanisms of chiral recognition in xenobiotic metabolism and drug‐receptor interactions

13C NMR spectra of 1,3‐oxathiolane, 1,3‐oxathiolane 3‐oxide and 1,3‐oxathiolane 3,3‐dioxide derivatives

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Product

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¹³C NMR spectra of 1,3‐oxathiolane, 1,3‐oxathiolane 3‐oxide and 1,3‐oxathiolane 3,3‐dioxide derivatives