Histamine Receptors

Casy, A. F.; Dewar, George H.

doi:10.1007/978-1-4899-2397-4_11

Cited by 4 publications

(4 citation statements)

References 83 publications

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“…It was shown earlier that modifications of Pro 2 in the sequence of EMs could yield proteolytically stable, yet MOP-active compounds, ,,− as such modifications do not alter the main pharmacophore groups. ,, Such modifications included the substitution of Pro 2 with 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic), pseudoprolines (ΨPro), six-membered heterocyclic rings, such as piperidine-2-, 3-, and 4-carboxylic acids (( S )-Pip, ( R )-Nip, and Inp, respectively), four-membered azetidine rings (Aze, 3Aze), and alicyclic β-amino acids (Acpc, 2-aminocyclopentane-1-carboxylic acid; Achc, 2-aminocyclohexane-1-carboxylic acid) (Figure ) . Systematic review of these results suggests the importance of ring structure and size in determining the bioactivity of the ligands.…”

Section: Introductionmentioning

confidence: 99%

The Effect of Pro² Modifications on the Structural and Pharmacological Properties of Endomorphin-2

et al. 2012

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Endomorphins (EM-1 and EM-2) are selective, high affinity agonists of the μ-opioid (MOP) receptor, an important target in pain regulation. Their clinical use is impeded by their poor metabolic stability and limited entry to the central nervous system. In this study, the Pro(2) residue of EM-2 was modified systematically through substitution by hydroxyproline (Hyp), (S)-β-homoproline (βPro), 2-aminocyclopentene-1-carboxylic acid (ΔAcpc), or 2-aminocyclohexene-1-carboxylic acid (ΔAchc) to obtain stable MOP active compounds. Both Hyp(2) and βPro(2) substitution decreased receptor affinity. Analogues incorporating alicyclic β-amino acids exhibited diverse receptor binding properties, depending on the configuration of the substituent side-chain. (1S,2R)ΔAcpc(2)-EM-2 was shown to have MOP affinity and selectivity comparable to those of EM-2 and proved to act as agonist while being resistant to proteolysis. NMR and molecular dynamics (MD) studies revealed that bent backbone structures are predominant in the most potent analogues, while their presence is less pronounced in ligands of lower receptor affinity.

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Section: Introductionmentioning

confidence: 99%

The Effect of Pro² Modifications on the Structural and Pharmacological Properties of Endomorphin-2

et al. 2012

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“…Nowadays, a number of efficient methods are available to the chemist for the synthesis of fluorinated molecules, thanks to the impressive development of new mild and chemoselective fluorinating agents, to the increasing commercial availability of novel fluorinated building blocks, and to the disclosure of new synthetic approaches to easily accessible fluorinated templates . On the other hand, despite the great impact of the “stereochemical factor” in modern medicinal chemistry and the preminent position of fluorinated molecules in the biomedicinal and pharmaceutical field, asymmetric synthesis in the area of fluoroorganic chemistry is still poorly developed . This is true both for the classical diastereoselective synthesis via chiral auxiliaries as well as for the enantioselective approach via chiral catalysts, enzymes, or living microorganisms, including the use of fluorinating agents, which are barely stereospecific …”

Section: Introductionmentioning

confidence: 99%

(R)-Trifluoro- and Difluoropyruvaldehyde N,S-Ketals: Chiral Synthetic Equivalents of β-Trifluoro and β-Difluoro α-Amino Aldehydes

et al. 1998

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A new, efficient, and stereoselective two-step approach to stereochemically defined chiral nonracemic gamma-tri- and gamma-difluoro beta-amino alcohols (70% to >95% ee) is described, using tri- and difluoropyruvaldehyde N,S-ketals (R)-1a,b as starting materials. Addition of Grignard reagents to (R)-1 occurs with moderate to excellent anti-stereocontrol, depending on the nature of the organomagnesium halides, providing the beta-p-tolylthio beta-benzyloxycarbonylamino secondary carbinols 5. The stereochemical outcome of these reactions can be rationalized by means of a chelated Cram's cyclic model, where the NCbz group is the chelating ligand and the p-tolylthio residue acts as the stereocontrolling "large" group. Reductive displacement of the 2-p-tolylthio substituent of 5 efficiently takes places by means of the NaBH(4)/pyridine system, probably via the corresponding intermediate transient imines 13, providing sulfur-free gamma-tri- and gamma-difluorinated beta-amino alcohols 7 with high levels of anti-stereoselectivity. A considerable shift toward syn-stereoselectivity was obtained performing the reaction on the corresponding phenylacetates 8. Cleavage and reduction of the NHCbz moiety of 7 provided tri- and difluoro analogues of, respectively, norephedrine (11) and ephedrine (12).

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“…Molecular recognition, which is the basis of biological activity, arises from the interactions of the substrate (drug) with the receptor site …”

Section: Introductionmentioning

confidence: 99%

Preparation of (R)-Fluoropyruvaldehyde N,S-Ketals by Highly Stereospecific Tandem Pummerer Rearrangement/1,2-p-Tolylthio Group Migration of (R)-α-(Fluoroalkyl)-β-sulfinylenamines

Volonterio

Zanda²,

Bravo³

et al. 1997

J. Org. Chem.

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Fluoropyruvaldehyde N,S-ketals (R)-2 have been prepared in good yields (up to 88%) and ee (up to 79%) from alpha-(fluoroalkyl)-beta-sulfinylenamines (R)-(Z)-1, through a new self-immolative tandem sequential process, consisting of a Pummerer reaction, promoted by trifluoroacetic anhydride, followed by a 1,2-migration of the p-tolylthio group, triggered by addition of silica gel or aqueous base. Each transfer of stereogenic center, from sulfur to the alpha-carbon and then to the beta-carbon, occurs with an average degree of enantioselectivity up to 94:6. Cis geometry between the sulfinyl and the amino groups of the starting enamine (R)-1 is necessary for achieving high level of stereocontrol, since neighboring group participation by the N-Cbz amino group prevents the sulfinyl center from racemization promoted by trifluoroacetic anhydride. NMR studies have shown that imines 3 are intermediate products of the Pummerer rearrangement, which are stable in the reaction environment.

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Histamine Receptors

Cited by 4 publications

References 83 publications

The Effect of Pro² Modifications on the Structural and Pharmacological Properties of Endomorphin-2

The Effect of Pro² Modifications on the Structural and Pharmacological Properties of Endomorphin-2

(R)-Trifluoro- and Difluoropyruvaldehyde N,S-Ketals: Chiral Synthetic Equivalents of β-Trifluoro and β-Difluoro α-Amino Aldehydes

Preparation of (R)-Fluoropyruvaldehyde N,S-Ketals by Highly Stereospecific Tandem Pummerer Rearrangement/1,2-p-Tolylthio Group Migration of (R)-α-(Fluoroalkyl)-β-sulfinylenamines

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Histamine Receptors

Cited by 4 publications

References 83 publications

The Effect of Pro2 Modifications on the Structural and Pharmacological Properties of Endomorphin-2

The Effect of Pro2 Modifications on the Structural and Pharmacological Properties of Endomorphin-2

(R)-Trifluoro- and Difluoropyruvaldehyde N,S-Ketals: Chiral Synthetic Equivalents of β-Trifluoro and β-Difluoro α-Amino Aldehydes

Preparation of (R)-Fluoropyruvaldehyde N,S-Ketals by Highly Stereospecific Tandem Pummerer Rearrangement/1,2-p-Tolylthio Group Migration of (R)-α-(Fluoroalkyl)-β-sulfinylenamines

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The Effect of Pro² Modifications on the Structural and Pharmacological Properties of Endomorphin-2

The Effect of Pro² Modifications on the Structural and Pharmacological Properties of Endomorphin-2