Stereoselectivity of muscarinic receptors in vivo and in vitro for oxotremorine analogs. N-[4-tert-amino-2-butynyl]-5-methyl-2-pyrrolidones

Amstutz, René; Ringdahl, Björn; Karlén, B; Roch, Margareth; Jenden, Donald J.

doi:10.1021/jm00150a004

Cited by 28 publications

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“…This observation contrasts with some recent results obtained with optically active analogues of oxotremorine in which a methyl group may substantially reinforce binding (Amstutz et al, 1985). In (-)-MCh, the methyl group clearly interferes with binding.…”

Section: Discussioncontrasting

confidence: 98%

“…The similar KA values ofACh and (+)-MCh (Table 2) indicate that the methyl-group at the chiral centre of (+ )-MCh does not enhance binding to the muscarinic receptor. This observation contrasts with some recent results obtained with optically active analogues of oxotremorine in which a methyl group may substantially reinforce binding (Amstutz et al, 1985). In (-)-MCh, the methyl group clearly interferes with binding.…”

Section: Discussioncontrasting

confidence: 98%

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Dissociation constants and relative efficacies of acetylcholine, (+)‐ and (‐)‐methacholine at muscarinic receptors in the guinea‐pig ileum

Ringdahl

1986

British J Pharmacology

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Dissociation constants (KA) and relative efficacies of acetylcholine, (+)‐methacholine and (‐)‐methacholine at muscarinic receptors in the guinea‐pig isolated ileum were determined in the absence and presence of the cholinesterase inhibitor diisopropylfluorophosphate. The method used involved analysis of dose‐response data before and after fractional inactivation of receptors with propylbenzilylcholine mustard. The KA values, estimated after cholinesterase inhibition, of acetylcholine, (+)‐ and (‐)‐methacholine were 1.7, 2.0 and 620 μM, respectively. The large (730 fold) difference in spasmogenic activity between (+)‐ and (‐)‐methacholine is due primarily to a difference in affinity for ileal muscarinic receptors although differences in efficacy (2 to 4 fold) also contribute. It is suggested that the methyl group at the chiral centre of (+)‐methacholine has no apparent effect on the binding to muscarinic receptors, whereas the corresponding methyl group of (‐)‐methacholine interferes with binding, presumably by stabilizing a conformation of the drug which does not fit the receptor very well.

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Section: Discussioncontrasting

confidence: 98%

Section: Discussioncontrasting

confidence: 98%

Dissociation constants and relative efficacies of acetylcholine, (+)‐ and (‐)‐methacholine at muscarinic receptors in the guinea‐pig ileum

Ringdahl

1986

British J Pharmacology

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“…Pyrrolenone 4c was synthesized from Cbz-protected proline following Andrus et al protocol (Scheme 4). Enantiomerically pure 5-methyl-2-pyrrolidinone was easily synthesized from commercially available 18 according to the conditions of Amstutz et al 10 The tripeptide carboxylic acid 3 was coupled with 4a, 4b, and 4c separately to produce 21, 22, and 23, respectively, in 67%, 73%, and 56% yields (Scheme 5). 6 Hydrochloric acid treatment produced the salt, which was then coupled with octanoic acid in the presence of BOPCl/Et 3 N to yield 24 ,11 25 ,12 and 26.…”

mentioning

confidence: 99%

Developing microcolin A analogs as biological probes

Mandal

Hines

Kuramochi

et al. 2005

Bioorganic & Medicinal Chemistry Letters

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Three microcolin A and B analogs have been synthesized. Their biological activity profiles were evaluated against several cell lines, revealing the existence of a structural determinant whose role in mediating the antiproliferative effect of the microcolins has heretofore gone unrecognized. While previously described as potent immunosuppressive natural products, we found that these microcolin analogs possessed no selective cytotoxicity when comparing immune cell versus nonimmune cell proliferation. In addition, the amino-terminus of microcolin A has been modified to incorporate a biotinylated polyethylene glycol linker. The biological activity of this biotinylated microcolin A analog was determined. This affinity reagent was shown to retain limited biological activity and thus can serve as a useful probe for elucidating the mechanism of action of microcolin A. KeywordsNatural products; Immunosuppressant; Synthesis Pharmacological intervention aimed at suppressing the immune system plays an important role in the management of autoimmune diseases, the prevention of rejection after organ transplantation, and treatment of graft versus host diseases. In recent years, many new immunosuppressive drugs have been discovered and developed for clinical use in organ transplantation. The commonly used immunosuppressive drugs fall into five groups with different mechanisms of action: (a) regulators of gene expression; (b) alkylating agents; (c) inhibitors of de novo purine synthesis; (d) inhibitors of de novo pyrimidine synthesis; and (e) inhibitors of kinases and phosphatases. Despite phenomenal success in this disease area, many of these drugs have troublesome side effects and high toxicity profiles. More effective and specific immunosuppressive therapy is needed to further reduce the high morbidity due to infections, malignancies, and graft loss due to chronic rejection after organ transplantation. Thus, the search for more efficacious and tolerant immunosuppressive drugs is vigorously pursued in both academia and pharmaceutical industry. In our chemical biology program, we are interested in developing natural products as biological probes to identify novel proteins for therapeutic intervention (target validation) and the exploration of cell biology (chemical genetics). 1Microcolins A and B are potent antiproliferative and immunosuppressive natural products discovered by Koehn and co-workers from the Venezuelan blue-green algae Lyngbya majuscule (Scheme 1). 2-4 Microcolins A and B were found to be potent in the human two- Microcolin A has been synthesized by Decicco and Grover 6 as well as by Andrus et al. 7 Koehn et al. 5 prepared several analogs by semisynthetic modification and/or degradation of the natural product. They showed that the C-10 free hydroxy functionality, as opposed to general oxygen functionality, is important for the biological activity. Striking loss of activity occurs upon reduction of the pyrrolenone ring C2-C3 olefin. The EC 50 value for 2,3-dihydromicrocolin A is 10,000-fold less potent than...

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“…Im Gegensatz zu der sonst iiblichen Substitution durch raumbeanspruchende Reste [5] ergab bereits die Einfuhrung einer Me-Gruppe in der 5 bzw. 1 Position in1 Oxotremorin-Gerust sehr potente uiid in der pharinakologischen Wirksamkeit dem Atropin iiberlegene muscarinische Agonisten [6]. ') Verschieden am 14.6.1987 In jungerer Zeit sind zentral wirksame selektive (MI/M2) muscarinische Verbindungen wieder im Gespriich.…”

Section: Position 5 At the Oxotremorine Skeleton As The Searing Positunclassified

“…Im Gegensatz zu I1 entsteht bei der Protonierung von IIla ein chirales Zentrum (s. . Vom isosterischen BOK-I ist bekannt, dass nur das (R)-Enantiomere potente antimuskarinische Wirkung zeigt [6]. Figur a ) .…”

Section: Nmeunclassified

Die Position 5 im Oxotremorin‐Gerüst: Eine zentrale Stelle für die Steuerung der Aktivität am muscarinischen Rezeptor

Amstutz

Closse

Gmelin

1987

Helvetica Chimica Acta

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Substitution of the CH2 group at position 5 of oxotremorine (2) by electronegative atoms like 0-or N-atom, or by sterically bulkier groups like methyl, N-formyl. or N-acetyl changes the pharmacological profile of oxotremorinc drastically. The 0and N-analogues were potent but unselective (M,/M,) muscarinic agonists. The methyl analogue ((R)-BOK-1) is a muscarine antagonist which is 10 times more potent on the ganglion cervical superius (pA2 = 9.3) than pirenzepine and is able to distinguish between the ileal and ganglion receptor by a factor of 100. The N-formyl derivative differentiates between the two receptors by a factor of 500 with a potency comparable to pirenzepine. The two MI-selective antagonists have higher affinity to the rat-ganglion receptors compared to the affinity to rat-cortex homogenate. The synthesis and the pharmacological activity of several new oxotremorine analogues are discussed.

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Stereoselectivity of muscarinic receptors in vivo and in vitro for oxotremorine analogs. N-[4-tert-amino-2-butynyl]-5-methyl-2-pyrrolidones

Cited by 28 publications

References 0 publications

Dissociation constants and relative efficacies of acetylcholine, (+)‐ and (‐)‐methacholine at muscarinic receptors in the guinea‐pig ileum

Dissociation constants and relative efficacies of acetylcholine, (+)‐ and (‐)‐methacholine at muscarinic receptors in the guinea‐pig ileum

Developing microcolin A analogs as biological probes

Die Position 5 im Oxotremorin‐Gerüst: Eine zentrale Stelle für die Steuerung der Aktivität am muscarinischen Rezeptor

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