Synthesis and substance P antagonist activity of naphthimidazolium derivatives

Lawrence, Kristine B.; Venepalli, Bhaskar R.; Appell, Kenneth C.; Goswami, Ramanuj; Logan, Margaret E.; Tomczuk, Bruce E.; Yanni, John M.

doi:10.1021/jm00085a015

Cited by 19 publications

(4 citation statements)

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“…Some of the naphth[2,3-d]imidazolium derivatives [236] such as 27, reported by Lawrence et. al. show that these analogs have comparable binding potency and tissue contractility to that of the corresponding imidazoquinoxalines [233].…”

Section: Non-peptide Antagonistsmentioning

confidence: 99%

Substance P: Structure, Function, and Therapeutics

Datar

Srivastava²,

Coutinho³

et al. 2004

CTMC

143

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Extensive efforts since 1931, on the structural determination of the mammalian tachykinin SP by NMR, CD and IR have turned out to be inconclusive. Studies are now being concentrated on the structural properties and characteristics of various NK receptors (NK(1), NK(2) and NK(3)) with the help of genetics, cloning, receptor engineering, mutagenesis and modeling. This knowledge is now being fruitfully used in the development of non-peptide NK(1) receptor antagonists that essentially block the pharmacological effects of SP. It is now being realized that the simultaneous blockade of two or more receptors gives promising results in emesis, depression and pulmonary obstructive diseases. In addition to the synthetic compounds, the discovery of antagonists from natural origin has added a great value to this field. In this review we have made an attempt to present the structural characteristics of SP, its analogs and antagonists, the structural characteristics of the NK receptor, and structure activity relationships that have helped to improve the therapeutic utilities of SP antagonists.

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Section: Non-peptide Antagonistsmentioning

confidence: 99%

Substance P: Structure, Function, and Therapeutics

Datar

Srivastava²,

Coutinho³

et al. 2004

CTMC

143

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“…Subsequent reaction conditions using THF led to the successful synthesis of the pyridinium product 39, which precipitated immediately upon formation from the reaction mixture. The phenylethynyl derivative 23 was obtained using a modified Pd-catalyzed cross coupling reaction previously applied to heteroaromatics such as halofurans.44 The Pdcatalyzed coupling between 4-bromopyridine (44) and phenylethyne in the presence of n-butyllithium, zinc chloride, and Pd [ (CgHgisP] 4 afforded 4-(1-phenylethynyl)pyridine (51), which subsequently was methylated to yield the corresponding pyridinium species 41. Reduction of Finally, the MAO-B substrate properties of the tetrahydropyridine derivatives 20-22 required the synthesis of the corresponding dihydropyridinium species, 52-54, for metabolite structure confirmation.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of novel MPTP analogs as potential monoamine oxidase B (MAO-B) inhibitors

Kalgutkar

Castagnoli²

1992

J. Med. Chem.

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The nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetahydropyridine (MPTP) is an excellent substrate and a weak inactivator of the flavoenzyme monoamine oxidase B (MAO-B). In an attempt to develop novel mechanism-based inactivators of MAO-B, we have synthesized analogs of MPTP bearing a variety of functional groups at either the N or the C(4) position and have examined their interactions with a purified MAO-B preparation isolated from beef liver. The substituents selected include allyl, propargyl, ethenyl, ethynyl, and cyclobutyl, that is, functionalities which were considered potential sources of enzyme generated electrophilic or radical intermediates that might alkylate and inactivate the enzyme. None of the C(4)-substituted compounds displayed significant enzyme inhibitor properties although some proved to be good substrates. In the N-substituted MPTP series only the 4-phenyl-1-propargyl analog was a good inhibitor. The time- and concentration-dependent inhibition of MAO-B displayed by this compound is consistent with a mechanism-based inactivation pathway and the catalytic mechanism currently held for monoamine oxidases. The results of these studies provide additional insights into the steric features of the active site of MAO-B and predict that the area in which the C(4) substituent of the tetrahydropyridine ring resides lacks a reactive nucleophilic group.

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“…Similarly, the amine substituents of CP-96,345, RP 67580 and SR 48968 may play a key role in binding to tachykinin receptors (Fong et al, 1993). Also the recently described non-peptide NKI receptor antagonists, WIN 51708 and WIN 62577 (Appell et al, 1992;Lawrence et al, 1992) have an amine substituent, being heterosteroid derivatives of imidazo [4,5-b] quinoxaline. After the first submission of this paper, a report appeared suggesting that CP-96,345 blocks sodium channels in neurones (Caeser et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

Non‐specific actions of the non‐peptide tachykinin receptor antagonists, CP‐96, 345, RP 67580 and SR 48968, on neurotransmission

Wang

Tung

Strichartz

et al. 1994

British J Pharmacology

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1 Three non-peptide tachykinin receptor antagonists, 345, RP 67580 and SR 48968, were found to inhibit the electrically-evoked, tachykinin-mediated contractile responses of the rabbit iris sphincter in a concentration-dependent fashion; the pIC" values were 5.6 ± 0.01, 5.4 ± 0.07 and 4.8 ± 0.03, respectively. 2 These antagonists also inhibited the electrically-evoked, parasympathetic response of the rabbit iris sphincter and the sympathetic response of the guinea-pig vas deferens in a concentration-dependent manner; the pICm values were 0.3-1.2 log units lower than those recorded for the tachykinin-mediated responses.3 Two local anaesthetics, bupivacaine and oxybuprocaine, were also found to inhibit the tachykininmediated, cholinergic and sympathetic contractile responses in these tissues in a concentration-dependent manner; the concentration ranges for producing the inhibition were similar to those of the non-peptide tachykinin receptor antagonists. 4 On the sciatic nerves of frogs, the tachykinin receptor antagonists inhibited action potentials in a concentration-dependent manner; the potency of the three drugs was similar to that of bupivacaine. 5 Our results suggest that, in addition to blocking tachykinin receptors, the non-peptide tachykinin receptor antagonists, CP-96,345, RP 67580 and SR 48968, may exert non-specific inhibitory effects on neurotransmission.

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Synthesis and substance P antagonist activity of naphthimidazolium derivatives

Cited by 19 publications

References 0 publications

Substance P: Structure, Function, and Therapeutics

Substance P: Structure, Function, and Therapeutics

Synthesis of novel MPTP analogs as potential monoamine oxidase B (MAO-B) inhibitors

Non‐specific actions of the non‐peptide tachykinin receptor antagonists, CP‐96, 345, RP 67580 and SR 48968, on neurotransmission

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