Synthesis, in vitro binding profile, and autoradiographic analysis of [3H]-cis-3-[(2-methoxybenzyl)amino]-2-phenylpiperidine, a highly potent and selective nonpeptide substance P receptor antagonist radioligand

Rosen, Terry; Seeger, Thomas; McLean, Stafford; Desai, Manoj C.; Guarino, Karen J.; Bryce, Dianne K.; Pratt, Kara G.; Heym, James; Chalabi, Philip M.

doi:10.1021/jm00073a022

Cited by 34 publications

(11 citation statements)

References 8 publications

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“…2 were kindly donated. CP96,345 and CP99,994 were provided by Dr. John A. Lowe III (Pfizer, Groton, CT) (Snider et al, 1991;Rosen et al, 1993). CGP49,823 was provided by Fig.…”

Section: Methodsmentioning

confidence: 99%

“…All mutations were verified by restriction endonucle- Bold, four amino acid residues common to all four tachykinin peptides. The lead compounds for the nonpeptide antagonists CP96,345 (Snider et al, 1991), CP99,994 (Rosen et al, 1993), RP67,580 (Garret et al, 1991), RPR100,893 (Tabert and Peyronel, 1994), LY303,870 (Gitter et al, 1995), and SR140,333 (Emonds-Alt et al, 1993b) were found by screening of chemical files, whereas the initial lead compounds for CGP49,823 (Schilling et al, 1993), CAM4092 (Boyle et al, 1994), and FK888 (Fujii et al, 1992) were peptide-based compounds.…”

Section: Methodsmentioning

confidence: 99%

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Steric Hindrance Mutagenesis versus Alanine Scan in Mapping of Ligand Binding Sites in the Tachykinin NK₁Receptor

et al. 1998

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Residues in transmembrane domain (TM)-III, TM-V, TM-VI, and TM-VII believed to be facing the deep part of the presumed main ligand-binding pocket of the NK 1 receptor were probed by alanine substitution and introduction of residues with larger and/or chemically distinct side chains. Unaltered or even improved binding affinity for four peptide agonists, substance P, substance P-O-methyl ester, eledoisin, and neurokinin A, as well as normal EC 50 values for substance P in stimulating phosphatidylinositol turnover indicated that these mutations did not alter the overall functional integrity of the receptor. The alanine substitutions in general had only minor effects on nonpeptide antagonist binding. However, the introduction of the larger and polar aspartic acid and histidine residues at positions corresponding to the monoamine binding aspartic acid in TM-III of the ␤ 2 -adrenoceptor (ProIII:08, Pro112 in the NK 1 receptor) and to the presumed monoamine interacting "two serines" in TM-V (ThrV:09, Thr201; and IleV:12, Ile204) impaired by Ͼ100-fold the binding of a group of nonpeptide antagonists, including CP96,345, CP99,994, RP67,580, RPR100,893, and CAM4092. In contrast, another group of nonpeptide antagonists, LY303,870, FK888, and SR140,333, were little or not at all affected by the space-filling substitutions. Two of these compounds, FK888 and LY303,870, were those most seriously affected (75-89-fold) by alanine substitution of PheVI:20 located in the upper part of the main ligand-binding crevice.

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“…2 were kindly donated. CP96,345 and CP99,994 were provided by Dr. John A. Lowe III (Pfizer, Groton, CT) (Snider et al, 1991;Rosen et al, 1993). CGP49,823 was provided by Fig.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Steric Hindrance Mutagenesis versus Alanine Scan in Mapping of Ligand Binding Sites in the Tachykinin NK₁Receptor

et al. 1998

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“…The pseudo‐enantiomeric catalyst 73 (derived from quinidine) produced ent ‐ 68a with comparable enantioselectivity. Enantiopure ent ‐ 68a can be transformed into unsaturated piperidine 74 and bicycle 75 , which are advanced intermediates in the synthesis of drugs candidates such as (+)‐CP‐99,994, (+)‐CP‐113,054, and (+)‐L‐733,060 (Scheme ) ,, . Additionally, through a 1,2‐aryl shift mediated by silver trifluoroacetate, piperidine 68d could be converted into 70 while preserving the ee .…”

Section: Thiocarbamate and Carbamate Catalystsmentioning

confidence: 99%

Lewis Base Catalyzed Stereo‐ and Regioselective Bromocyclization

Gieuw

Yeung

2016

The Chemical Record

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Oxygen- and nitrogen-containing heterocyclic compounds are widely recognized as key components in many natural products and biologically relevant molecules, but often the problem comes down to methodologies in synthesizing them. Halocyclization of olefinic substrates is a promising strategy in the construction of O- and N-heterocyclic compounds, which further signifies the development of their asymmetric variants. Over the past years, our group has been devoted to this particular area of asymmetric electrophilic halocyclization with chalcogen-containing molecules as catalysts. In this account, the main focus is on the development of our novel chiral catalysts and applications derived from the reaction products.

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“…For example, the piperidine alkaloid pseudodistomin A 1 , which was isolated from tunicates, exhibits calmodulin antagonistic activity, and therefore strongly depresses tumor growth in vitro . The racemic compound CP-99,994 2 was recently discovered as the most potent antagonist of substance P, an undecapeptide, which acts as a neurotransmitter in the central and peripheral nervous system and is involved in smooth muscle contraction and regulation of immune responses we were interested in whether this reaction type could be extended to the syntheses of 2,3,4-trisubstituted piperidines 3 bearing an amino group at C-3 (Scheme ).…”

Section: Introductionmentioning

confidence: 99%

Preparation of 2,3,4-Trisubstituted Piperidines by a Formal Hetero-Ene Reaction of Amino Acid Derivatives

1996

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N-Benzyl- or N-tosyl-N-(4-methyl-3-pentenyl)amino aldehyde benzylimines, which are obtained from alanine, leucine, or phenylalanine methyl esters in five steps, can be cyclized diastereoselectively in the presence of Lewis acids to give 3-amino-2,4-dialkyl-substituted piperidines. The product distribution and diastereoselectivity depends on the type of Lewis acid and nitrogen-protecting group. Benzyl-protected imines give 2-alkyl-3-(benzylamino)-4-isopropenyl piperidines with FeCl(3) and 2-alkyl-3-(benzylideneamino)-4-isopropylpiperidines with TiCl(4). Tosyl-protected imines show a decreased level of selectivity. The relative configurations of the piperidines were established by NMR and X-ray crystal structure analyses. Iminium ion cyclization followed by two competitive ionic pathways, i.e. either proton elimination or hydride transfer are discussed for these reactions.

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Synthesis, in vitro binding profile, and autoradiographic analysis of [3H]-cis-3-[(2-methoxybenzyl)amino]-2-phenylpiperidine, a highly potent and selective nonpeptide substance P receptor antagonist radioligand

Cited by 34 publications

References 8 publications

Steric Hindrance Mutagenesis versus Alanine Scan in Mapping of Ligand Binding Sites in the Tachykinin NK₁Receptor

Steric Hindrance Mutagenesis versus Alanine Scan in Mapping of Ligand Binding Sites in the Tachykinin NK₁Receptor

Lewis Base Catalyzed Stereo‐ and Regioselective Bromocyclization

Preparation of 2,3,4-Trisubstituted Piperidines by a Formal Hetero-Ene Reaction of Amino Acid Derivatives

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Synthesis, in vitro binding profile, and autoradiographic analysis of [3H]-cis-3-[(2-methoxybenzyl)amino]-2-phenylpiperidine, a highly potent and selective nonpeptide substance P receptor antagonist radioligand

Cited by 34 publications

References 8 publications

Steric Hindrance Mutagenesis versus Alanine Scan in Mapping of Ligand Binding Sites in the Tachykinin NK1Receptor

Steric Hindrance Mutagenesis versus Alanine Scan in Mapping of Ligand Binding Sites in the Tachykinin NK1Receptor

Lewis Base Catalyzed Stereo‐ and Regioselective Bromocyclization

Preparation of 2,3,4-Trisubstituted Piperidines by a Formal Hetero-Ene Reaction of Amino Acid Derivatives

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Product

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Steric Hindrance Mutagenesis versus Alanine Scan in Mapping of Ligand Binding Sites in the Tachykinin NK₁Receptor

Steric Hindrance Mutagenesis versus Alanine Scan in Mapping of Ligand Binding Sites in the Tachykinin NK₁Receptor