The separation of 3H-Benzodiazepine binding sites in brain and of benzodiazepine pharmacological properties

Dubnick, Bernard; Lippa, Arnold S.; Klepner, Claire A.; Coupet, Joseph; Greenblatt, E. N.; Beer, Bernard

doi:10.1016/0091-3057(83)90385-4

Cited by 36 publications

(8 citation statements)

References 36 publications

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“…This very promising result led us to examine the synthesis and bioactivities of the corresponding cyclic heptapeptides of the general structure Ac-[Nle4,Xxx5,D-Phe7,Yyy10]-a-MSH4_10-NH2. These truncated analogues were prepared to investigate the contribution of the [11][12][13] residues on the potency and prolonged biological activity of this new cyclic series, as well as the importance of the ring size and the side-chain substitutions on the biological activity in this cyclic lactam series (Table I). Ac-[Nle4,GÍu5,D-Phe7,Lys10]-a-MSH4_10-NH2 (IV) (24-mem-bered ring) was found to have 0.5 and 9 times the potency of -MSH in the frog and lizard skin bioassays, respectively, and the duration of action of peptide IV was prolonged in both assays (Table I).…”

Section: Scheme Imentioning

confidence: 99%

Potent and prolonged-acting cyclic lactam analogs of .alpha.-melanotropin: design based on molecular dynamics

Al‐Obeidi¹,

Castrucci²,

Hadley³

et al. 1989

J. Med. Chem.

324

272

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Utilizing results from previous structure-activity relationships and theoretical studies of alpha-melanotropin (alpha-MSH, Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2) and its related superpotent analogues, Ac-[Nle4,D-Phe7]-alpha-MSH and Ac-[Cys4,Cys10]-alpha-MSH, we have designed a new class of alpha-MSH4-13 and alpha-MSH4-10 cyclic lactam fragment analogues of alpha-melanotropin. The cyclic peptides have the following general structures: Ac-[Nle4,Xxx5,D-Phe7,Yyy10,Gly11]-alpha-MSH4-13- NH2 and Ac-[Nle4,Xxx5,D-Phe7,Yyy10]-alpha-MSH4-10-NH2, where Xxx = Glu or Asp and Yyy = Lys, Orn, Dab, or Dpr. Formation of the lactam bridge between the side-chain groups Xxx and Yyy was performed either in solution or on a solid-phase support. Seven cyclic peptides were prepared and bioassayed for their melanotropic potency by using standard frog (Rana pipiens) and lizard (Anolis carolinensis) skin bioassays. Relative to alpha-MSH (relative potency = 1), the potencies of the cyclic peptides in the lizard skin bioassay were as follows: alpha-MSH (1); Ac-[Nle4,Glu5,D-Phe7,Lys10,Gly11]-alpha-MSH4-13- NH2 (6); Ac-[Nle4,Asp5,D-Phe7,Lys10,Gly11]-alpha-MSH4-13- NH2 (100); Ac-[Nle4,Glu5,D-Phe7,Lys10]-alpha-MSH4-10-NH2 (9); Ac-[Nle4,Asp5,D-Phe7,Lys10]-alpha-MSH4-10-NH2 (90); Ac-[Nle4,Asp5,D-Phe7,Orn10]-alpha-MSH4-10-NH2 (20); Ac-[Nle4,Asp5,D-Phe7,Dab10]-alpha-MSH4-10-NH2 (5); Ac-[Nle4,Asp5,D-Phe7,Dpr10]-alpha-MSH4-10-NH2 (5). Similar results were obtained in the frog skin bioassay, but the analogues were much less potent. Cyclic melanotropins with 23-membered rings exhibited 100-fold higher melanotropic potency than alpha-MSH with selectivity for the lizard melanocyte receptors over the frog melanocyte receptors. Increasing or decreasing the ring size of these cyclic melanotropins from 23 diminishes the biological potency of the resulting cyclic peptide. The 23- and 24-membered ring analogues showed prolonged (residual) biological activities in both biological assays, but the smaller ring systems (20, 21, 22) did not. These results provide new insights into the structural and conformational requirements of alpha-MSH and its analogues at two different types of pigment cell (melanocyte) receptors.

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Section: Scheme Imentioning

confidence: 99%

Potent and prolonged-acting cyclic lactam analogs of .alpha.-melanotropin: design based on molecular dynamics

Al‐Obeidi¹,

Castrucci²,

Hadley³

et al. 1989

J. Med. Chem.

324

272

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“… 4 The high interest in this compound class in medicinal chemistry and medicine made many BzD analogues synthetically accessible and established a rich body of literature on their pharmacological properties. 5 , 6 , 7 A variety of biological activities and synthetic routes have also been established for the related benzotriazepines (BzT). 8 …”

Section: Introductionmentioning

confidence: 99%

Benzodiazepines and benzotriazepines as protein interaction inhibitors targeting bromodomains of the BET family

Filippakopoulos

Picaud

Fedorov

et al. 2012

Bioorganic & Medicinal Chemistry

113

111

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“…BZDs consist of a benzene ring fused to a diazepine – a seven-membered heterocycle containing two nitrogen atoms, typically at positions 1 and 4 on the ring (Figure 1A). From a clinical perspective, the BZD is regarded as a proven privileged scaffold because it appears in many drugs that have been used for decades for anticonvulsant, sedative, and anxiolytic purposes (Bermak et al, 2007; Dubnick et al, 1983; Olkkola and Ahonen, 2008; Wang et al, 1999). Among the most widely known and prescribed members of the BZD family are diazepam, alprazolam, lorazepam, and chlordiazepoxide (Figure 1B) (Atack, 2005; Olkkola and Ahonen, 2008; Verster and Volkerts, 2004; VonVoigtlander and Straw, 1985).…”

mentioning

confidence: 99%

Privileged Diazepine Compounds and Their Emergence as Bromodomain Inhibitors

Smith

Sánchez

Zhou

2014

Chemistry & Biology

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Chemical compounds built on a diazepine scaffold have recently emerged as potent inhibitors of the acetyl-lysine binding activity of bromodomain-containing proteins, which is required for gene transcriptional activation in cancer and inflammation. Not only have these chemical compounds validated bromodomains as attractive epigenetic drug targets, but they have also brought to the forefront another application of the diazepine, which had already been regarded as a versatile chemical scaffold in rational drug design. This article reviews the success of diazepine compounds as therapeutic agents and examines the unique chemical and geometric features of this privileged scaffold that make it an excellent template for developing potent and selective molecules that control bromodomain-related gene expression in human diseases.

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The separation of 3H-Benzodiazepine binding sites in brain and of benzodiazepine pharmacological properties

Cited by 36 publications

References 36 publications

Potent and prolonged-acting cyclic lactam analogs of .alpha.-melanotropin: design based on molecular dynamics

Potent and prolonged-acting cyclic lactam analogs of .alpha.-melanotropin: design based on molecular dynamics

Benzodiazepines and benzotriazepines as protein interaction inhibitors targeting bromodomains of the BET family

Privileged Diazepine Compounds and Their Emergence as Bromodomain Inhibitors

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