Tricyclic compounds as selective muscarinic receptor antagonists. 3. Structure-selectivity relationships in a series of cardioselective (M2) antimuscarinics

Engel, Wolfhard; Eberlein, Wolfgang; Mihm, Gerhard; Hammer, Rudolf; Trummlitz, Guenter

doi:10.1021/jm00128a008

Cited by 39 publications

(16 citation statements)

References 5 publications

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“…Methoctramine ( Melchiorre et al ., 1987 ), spirotramine ( Melchiorre et al ., 1995 ), dipitramine and tripitramine ( Melchiorre et al ., 1993 ; Minarini et al ., 1994 ), AM172, AM170, CC7, CC8 and CC9 ( Bolognesi et al ., 1998 ) were synthesized in the Department of Pharmaceutical Sciences of the University of Bologna. Pirenzepine dihydrochloride and McN‐A‐343 were synthesized according to the literature ( Engle et al ., 1989 ; Nilsson et al ., 1992 ).…”

Section: Methodsmentioning

confidence: 99%

Analysis of the muscarinic receptor subtype mediating inhibition of the neurogenic contractions in rabbit isolated vas deferens by a series of polymethylene tetra‐amines

Budriesi

Cacciaguerra

Toro

et al. 2001

British J Pharmacology

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The pharmacological characteristics of the presynaptic muscarinic receptor subtype, which mediates inhibition of the neurogenic contractions in the prostatic portion of rabbit vas deferens, have been investigated by using a series of polymethylene tetra‐amines, which were selected for their ability to differentiate among muscarinic receptor subtypes. It was found that all tetra‐amines antagonized McN‐A‐343‐induced inhibition in electrically stimulated rabbit vas deferens in a competitive manner and with affinity values (pA2) ranging between 6.27±0.09 (spirotramine) and 8.51±0.02 (AM170). Competition radioligand binding studies, using native muscarinic receptors from rat tissues (M1, cortex; M2, heart; M3, submaxillary gland) or from NG 108‐15 cells (M4) and human cloned muscarinic M1‐M4 receptors expressed in CHO‐K1 cells, were undertaken with the same tetra‐amines employed in functional assays. All antagonists indicated a one‐site fit. The affinity estimates (pKi) of tetra‐amines calculated in binding assays using native receptors were similar to those obtained using cloned receptors. Among these compounds some displayed selectivity between muscarinic receptor subtypes, indicating that they may be valuable tools in receptor characterization. Spirotramine was selective for M1 receptors versus all other subtypes (pKi native: M1, 7.32±0.10; M2, 6.50±0.11; M3, 6.02±0.13; M4, 6.28±0.16; pKi cloned: M1, 7.69±0.08; M2, 6.22±0.14; M3, 6.11±0.16; 6.35±0.11) whereas CC8 is highly selective for M2 receptors versus the other subtypes (pKi native: M1, 7.50±0.04; M2, 9.01±0.12; M3, 6.70±0.08; M4, 7.56±0.04; pKi cloned: M1, 7.90±0.20; M2, 9.04±0.08; M3, 6.40±0.07; M4, 7.40±0.04). Furthermore, particularly relevant for this investigation were tetra‐amines dipitramine and AM172 for their ability to significantly differentiate M1 and M4 receptors. The apparent affinity values (pA2) obtained for tetra‐amines in functional studies using the prostatic portion of rabbit vas deferens correlated most closely with the values (pKi) obtained at either native or human recombinant muscarinic M4 receptors. This supports the view that the muscarinic receptor mediating inhibition of neurogenic contractions of rabbit vas deferens may not belong to the M1 type but rather appears to be of the M4 subtype. British Journal of Pharmacology (2001) 132, 1009–1016; doi:

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Section: Methodsmentioning

confidence: 99%

Analysis of the muscarinic receptor subtype mediating inhibition of the neurogenic contractions in rabbit isolated vas deferens by a series of polymethylene tetra‐amines

Budriesi

Cacciaguerra

Toro

et al. 2001

British J Pharmacology

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“…AF‐DX 116 and AF‐DX 384 (Figure 2) are M 2 ‐preferring antagonists with a selectivity profile of M 2 greater than M 1 greater than M 3 (Eberlein et al. , 1989; Engel et al. , 1989).…”

Section: Muscarinic Ligands Heralding An Allosteric/orthosteric Bindimentioning

confidence: 99%

Rational design of dualsteric GPCR ligands: quests and promise

Mohr

Tränkle

Kostenis

et al. 2010

British J Pharmacology

109

119

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Dualsteric ligands represent a novel mode of targeting G protein-coupled receptors (GPCRs). These compounds attach simultaneously to both, the orthosteric transmitter binding site and an additional allosteric binding area of a receptor protein. This approach allows the exploitation of favourable characteristics of the orthosteric and the allosteric site by a single ligand molecule. The orthosteric interaction provides high affinity binding and activation of receptors. The allosteric interaction yields receptor subtype-selectivity and, in addition, may modulate both, efficacy and intracellular signalling pathway activation. Insight into the spatial arrangement of the orthosteric and the allosteric site is far advanced in the muscarinic acetylcholine receptor, and the design of dualsteric muscarinic agonists has now been accomplished. Using the muscarinic receptor as a paradigm, this review summarizes the way from suggestive evidence for an orthosteric/allosteric overlap binding to the rational design and experimental validation of dualsteric ligands. As allosteric interactions are increasingly described for GPCRs and as insight into the spatial geometry of ligand/GPCR-complexes is growing impressively, the rational design of dualsteric drugs is a promising new approach to achieve fine-tuned GPCR-modulation.

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“…Basically, this class of compounds have 1,4-benzodiazepine-5-one skeleton which is fused to a pyrimidine ring. Such fused benzodiazepines posses a variety of therapeutic activities like HIV-1 reverse transcriptase and muscarinic receptor inhibition [71] and some of the compounds have been used for different disease conditions like ulcer treatment [72][73][74][75] (Fig. (5)).…”

Section: Pyrrolo[21-c][14]benzodiazepine-5-ones and 511-dionesmentioning

confidence: 99%

Recent Advances in the Solid-Phase Combinatorial Synthetic Strategies for the Benzodiazepine Based Privileged Structures

Kamal¹,

Reddy

Devaiah³

et al. 2006

MRMC

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Benzodiazepine based heterocycles can be prepared efficiently on solid-support by employing different approaches. In this review, an effort has been made to highlight academic and industrial examples of combinatorial synthesis for this type of heterocycles published in the last decade. Therefore, it describes synthetic strategies for the generation of benzodiazepine privileged structures employing the corresponding resin-bound substrates. Further, the most relevant biological properties of these heterocycles have also been incorporated.

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Tricyclic compounds as selective muscarinic receptor antagonists. 3. Structure-selectivity relationships in a series of cardioselective (M2) antimuscarinics

Cited by 39 publications

References 5 publications

Analysis of the muscarinic receptor subtype mediating inhibition of the neurogenic contractions in rabbit isolated vas deferens by a series of polymethylene tetra‐amines

Analysis of the muscarinic receptor subtype mediating inhibition of the neurogenic contractions in rabbit isolated vas deferens by a series of polymethylene tetra‐amines

Rational design of dualsteric GPCR ligands: quests and promise

Recent Advances in the Solid-Phase Combinatorial Synthetic Strategies for the Benzodiazepine Based Privileged Structures

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