The cardio-selectivity of himbacine: a muscarine receptor antagonist

Anwar-ul, S.; Gilani, Anwarul Hassan; Cobbin, L. B.

doi:10.1007/bf00633191

Cited by 142 publications

(25 citation statements)

References 7 publications

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“…The M2 subtype appears heterogeneous in both functionai and biochemical studies. In fact, cardiac muscarinic receptors differ so extensively from those of smooth muscle and exocrine glands in their properties as to suggest the existence ofdistinct subtypes (Barlow et al, 1976;Stockton et al, 1983;Mutschler & Lambrecht, 1984;Anwar-ul et al, 1986;Giachetti et al, 1986;Hammer et al, 1986). However, since our study is mainly concerned with drugs interacting with the Ml subtype, the receptors which display low affinity for pirenzepine are generically termed peripheral muscarinic subtypes in the context of this paper.…”

Section: Discussionmentioning

confidence: 93%

Binding and functional profiles of the selective M₁ muscarinic receptor antagonists trihexyphenidyl and dicyclomine

Giachetti

Giraldo

Ladinsky

et al. 1986

British J Pharmacology

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1 The selectivity profiles of the muscarinic receptor antagonists dicyclomine and trihexypbenidyl have been examined in binding and functional studies and compared with those of pirenzepine and atropine. Thus, the drugs appeared to discriminate between the Ml (cortical) and the peripheral muscarinic subtypes (cardiac and glandular). However, atropine displayed similar affinities for either subtype with IC50s varying only slightly (1.6-4.6 nM). The rank order of selectivity was: pirenzepine > dicyclomine > trihexyphenidyl > atropine. 4 Mirroring the binding data, pirenzepine, dicyclomine and trihexyphenidyl showed a tenfold greater ability at inhibiting M,-receptor mediated ganglionic responses (McN A-343 pressor effect in pithed rats and nictitating membrane contraction in cats) than at inhibiting peripheral muscarinic responses in the heart and cardiovascular smooth muscle (vagal bradycardia in rats and cats and vagally-induced vasodilatation in cats).5 The muscarinic antagonists so far examined can be categorized into two groups. Trihexyphenidyl, dicyclomine and pirenzepine, included in one group, are characterized by a higher affinity for the neuronal (MI) muscarinic receptor, hence they antagonize functional responses mediated by the Ml subtype. Atropine, a member of the other group, shows essentially no selectivity. 6 Differentiation of M1 and peripheral muscarinic receptor subtypes appears to be a property not confined to tricyclics such as pirenzepine but shared by diverse chemical structures. Both trihexyphenidyl and dicyclomine appear to be useful pharmacological tools in the classification of muscarinic receptor subtypes.

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Section: Discussionmentioning

confidence: 93%

Binding and functional profiles of the selective M₁ muscarinic receptor antagonists trihexyphenidyl and dicyclomine

Giachetti

Giraldo

Ladinsky

et al. 1986

British J Pharmacology

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“…Using autoradiographic techniques, we have shown that in a cell culture preparation of guinea-pig atria, muscarinic receptors are present on all intracardiac neurones and atrial myocytes (Hassall, Buckley & Burnstock, 1987). The receptors present on mammalian cardiac muscle have been shown to be of a predominantly M2 subtype, characterized as having a low affinity for pirenzepine and a high affinity for the antagonist 11 - [[2 -[(diethylamino)methyl] -1 -piperidinyl]acetyl] -5,11 -dihydro -6H-pyrido [2,3-b][1,4]benzodiazepine-6-one (AF-DX 116) and himbacine (Anwar- UL, Gilani & Gobbin, 1986;. However, a small percentage of the muscarinic receptors in the heart were found to be of the M1 subtype, a type commonly found within autonomic ganglia (Watson, Yamamura & Roeske, 1983).…”

Section: Introductionmentioning

confidence: 99%

M1 and M2 muscarinic receptors mediate excitation and inhibition of guinea‐pig intracardiac neurones in culture.

Allen

Burnstock

1990

The Journal of Physiology

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SUMMARY1. The effects of muscarine upon intracardiac neurones cultured from ganglia within the atria and interatrial septum of the newborn guinea-pig heart were studied using intracellular recording techniques.2. Muscarine applied to the neuronal soma typically produced a biphasic change in membrane potential which consisted of a small hyperpolarization followed by a (lepolarization. In addition, muscarine (0 01-10 /tM) inhibited the calcium-dependent, after-hyperpolarization (AHP) and greatly increased the number of action potentials that could be evoked by a given depolarizing current.3. The hyperpolarization was associated with a decrease in input resistance and it reversed to become a depolarization at a potential of -865 mV. This response was antagonized by 4-diphenylacetoxy-N-methyl-piperidine (4-DAMP; 100 nM) and AF-DX 116 (500 nM), but was unaffected by pirenzepine (0 1-5 ftM).4. Two types of slow depolarization were observed in the presence of muscarine. The most common was associated with an increase in input resistance in the potential range -70 to -40 mV. Pirenzepine (100 nM) selectively antagonized this response, 4-DAMP (100 nM) similarly antagonized the response, but was non-selective. AF-DX 116 (0 5-5 /IM) showed no antagonist effect. The less common depolarization (5 % of cells) had a long latency and was associated with a decrease in input resistance.5. Muscarine reduced the duration of the action potential and inhibited the AHP.Cadmium chloride (100,UM) mimicked these actions of muscarine. Application of muscarine immediately following a train of action potentials did not inhibit the AHP, suggesting that muscarine did not directly inhibit the calcium-activated potassium current (VK(Ca)). Muscarine-induced depression of the slow AHP was antagonized by 4-DAMP (100 nM) but was not antagonized by either pirenzepine (01-05,um) orAF-DX 116 (05-5/tM).6. It is concluded that the muscarine-induced depolarization of guinea-pig intracardiac neurones results from reduction of a potassium conductance similar to the M-conductance, through activation of M1 muscarinic receptors. The hyper-

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“…Both these antagonists were more potent on ileum than on atrium. Only gallamine had the reverse selectivity but results obtained with this compound are difficult to interpret due to its allosteric activity (Stockton et al, 1983 (Giachetti et al, 1986), methoctramine (N,N'-bis[6-[(2-methoxybenzyl)amino]-hexyl]-1,8 -octanediamine tetrahydrochloride) (Melchiorre et al, 1987) and himbacine (Anwar-ul et al, 1986).…”

Section: Introductionmentioning

confidence: 99%

Functional and binding studies with muscarinic M₂‐subtype selective antagonists

Lazareno¹,

Roberts²

1989

British J Pharmacology

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1 The potency of a series of selective muscarinic antagonists has been measured on two functional isolated tissue preparations (rat ileum and atria) and these compared with their potency on a range of binding preparations in order to determine whether the subtypes of M2 receptor measured functionally are the same as those measured in binding studies. 2 On the functional preparations pirenzepine, hexahydrosiladiphenidol (HSD) and 4-diphenylacetoxy-N-methylpiperidine (4-DAMP) were more potent on the ileum than on the atrium (3 fold, 29 fold and 5 fold respectively), whereas himbacine, AF-DX 116 and methoctramine showed the opposite selectivity (5 fold, 3 fold and 56 fold respectively). Atropine had a similar potency on the ileum and atrium. 3 [3H]-N-methyl scopolamine was used to study M2 binding sites on membranes from rat heart and rat submandibular gland. Each preparation appeared to contain a homogeneous binding site population. The potencies of the five M2 selective antagonists (and pirenzepine) in binding studies to heart membranes were very similar to those observed in functional studies of rat atria (correlation coefficient = 0.98). Similarly the binding to submandibular gland membranes was very similar to that observed in functional studies on rat ileum (correlation coefficient = 0.97). 4 [3H]-pirenzepine was used to examine the binding of these antagonists to M1 binding sites on membranes from rat cerebral cortex. The affinities of 4-DAMP, HSD, AF,-DX1 16 and himbacine at M1 sites were similar to their affinities on the gland. Only pirenzepine and methoctramine had higher affinity on Ml sites than on the gland.5 Himbacine had a 20 fold lower affinity at M1 binding sites than at heart sites, and it should therefore be an important tool in identifying M1 sites. 6 Inhibition of [3H]-N-methyl scopolamine binding to rat ileum and rat brainstem by M2-selective antagonists was best described by a two-site model. In both cases the major population of sites (70-90%) appeared to be similar to sites found on the heart (correlation coefficients = 0.95 and 0.97). The other site appeared to be similar to that on the submandibular gland (correlation coefficients = 0.96 and 1.00). 7 The correlations observed in these studies in which a range of selective muscarinic antagonists was used lend weight to previous studies indicating the presence of three functionally important muscarinic receptor subtypes, typified by the binding sites studied in the cerebral cortex, submandibular gland and heart. 8 We propose that the sub-classification of the M2 muscarinic receptor into M2 and M3 subtypes on the basis of ligand binding studies should be extended to cover functionally-defined receptors as well.

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The cardio-selectivity of himbacine: a muscarine receptor antagonist

Cited by 142 publications

References 7 publications

Binding and functional profiles of the selective M₁ muscarinic receptor antagonists trihexyphenidyl and dicyclomine

Binding and functional profiles of the selective M₁ muscarinic receptor antagonists trihexyphenidyl and dicyclomine

M1 and M2 muscarinic receptors mediate excitation and inhibition of guinea‐pig intracardiac neurones in culture.

Functional and binding studies with muscarinic M₂‐subtype selective antagonists

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The cardio-selectivity of himbacine: a muscarine receptor antagonist

Cited by 142 publications

References 7 publications

Binding and functional profiles of the selective M1 muscarinic receptor antagonists trihexyphenidyl and dicyclomine

Binding and functional profiles of the selective M1 muscarinic receptor antagonists trihexyphenidyl and dicyclomine

M1 and M2 muscarinic receptors mediate excitation and inhibition of guinea‐pig intracardiac neurones in culture.

Functional and binding studies with muscarinic M2‐subtype selective antagonists

Contact Info

Product

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Binding and functional profiles of the selective M₁ muscarinic receptor antagonists trihexyphenidyl and dicyclomine

Binding and functional profiles of the selective M₁ muscarinic receptor antagonists trihexyphenidyl and dicyclomine

Functional and binding studies with muscarinic M₂‐subtype selective antagonists