Benzazepinone calcium channel blockers. 2. Structure activity and drug metabolism studies leading to potent antihypertensive agents. Comparison with benzothiazepinones

Floyd, David M.; Kimball, S. David; Krapcho, John; Das, Jagabandhu; Turk, Chester F.; Moquin, Robert V.; Lago, Michael W.; Duff, Keith J.; Lee, Ving G.

doi:10.1021/jm00082a018

Cited by 67 publications

(32 citation statements)

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“…Indeed, the diltiazem scaffold is amenable to medicinal chemistry, as shown previously (Floyd et al, 1992). The divergence between GHSR1a activity and L-type Ca 2ϩ channel binding activity (Schoemaker et al, 1987) observed in the structural analogs tested here demonstrates the potential for developing potent GHSR1a agonists lacking Ltype Ca 2ϩ channel blocking activity from the diltiazem scaffold.…”

supporting

confidence: 55%

Identification of the Atypical L-Type Ca²⁺ Channel Blocker Diltiazem and Its Metabolites As Ghrelin Receptor Agonists

et al. 2007

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Using a high-throughput functional screen, the atypical L-type Ca 2ϩ channel blocker diltiazem was discovered to be an agonist at the human ghrelin (GHSR1a) receptor. In cellular proliferation, Ca 2ϩ mobilization, and bioluminescence resonance energy transfer (BRET-2) assays, diltiazem was a partial agonist at GHSR1a receptors, with 50 to 80% relative efficacy compared with the GHSR1a peptide agonist GHRP-6, and high nanomolar to low micromolar potency, depending upon the assay. Seven of the known primary metabolites of diltiazem were synthesized, and three of them (M A , M 1 , and M 2 ) were more efficacious and/or more potent than diltiazem at GHSR1a receptors, with a rank order of agonist activity of M 2 Ͼ M 1 Ͼ M A Ͼ diltiazem, whereas M 4 and M 6 metabolites displayed weak agonist activity, and the M 8 and M 9 metabolites were inactive. Binding affinities of diltiazem and these metabolites to GHSR1a receptors followed a similar rank order. In vivo tests showed that diltiazem and M 2 each stimulated growth hormone release in male Sprague-Dawley neonatal rats, although to a lesser degree than GHRP-6. Thus, diltiazem and chemical analogs of diltiazem represent a new class of GHSR1a receptor agonists. The possible contributions of GHSR1a receptor activation to the clinical actions of diltiazem are discussed in the context of the known beneficial cardiovascular effects of ghrelin.Receptors that mediate the effects of growth hormone secretagogues (GHSs), including modified enkephalin peptides (Bowers et al., 1984) as well as small molecules (Smith et al., 1993), each capable of stimulating GH release, were only recently cloned (Howard et al., 1996). Two isoforms (A and B) were identified, but only growth hormone secretagogue receptor type 1a (GHSR1a) binds and responds to GHSs (Howard et al., 1996). Both isoforms are widely expressed, with the highest levels of GHSR1a found in the arcuate nucleus of the hypothalamus, and lower levels in cardiac tissue (Guan et al., 1997;Gnanapavan et al., 2002). Subsequently, a naturally occurring GHSR1a agonist was identified called ghrelin (Kojima et al., 1999).A great deal of evidence exists linking ghrelin, GHSR1a receptors, food intake, and obesity in both animal models (Tschöp et al., 2000;Nakazato et al., 2001;Asakawa et al., 2003;Shearman et al., 2006) and humans (Cummings et al., 2001(Cummings et al., , 2002Wren et al., 2001). However, ghrelin also regulates a variety of other endocrine and metabolic processes, including gut motility, energy homeostasis, cellular proliferation, and hormone production (for review, see van der Lely et al., 2004). It is noteworthy that ghrelin, and other GHS ligands produce a number of beneficial effects on cardiovasArticle, publication date, and citation information can be found at http://molpharm.aspetjournals.org. doi:10.1124/mol.107.034298. ABBREVIATIONS: GHS

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confidence: 55%

Identification of the Atypical L-Type Ca²⁺ Channel Blocker Diltiazem and Its Metabolites As Ghrelin Receptor Agonists

et al. 2007

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“…Random Docking-For the ligand-docking computational experiments we have chosen one of the most potent BTZ derivatives, SQ32910 (14,18). Random docking of the ligand in the open channel was performed using the multi-MCM method as described previously (29,32).…”

Section: Resultsmentioning

confidence: 99%

“…The ligand-Ca 2ϩ coordination can explain the above SAR peculiarity as well as the potentiation of diltiazem binding by Ca 2ϩ (7). Replacements of the ammonium group by hydrophilic groups significantly decreased the BTZ potency, suggesting a nucleophilic site in the receptor (14). Two nucleophilic sites are Experimentally found BTZ-sensing residues (1, 2, and 7) are bold.…”

Section: Discussionmentioning

confidence: 99%

Molecular Modeling of Benzothiazepine Binding in the L-type Calcium Channel

Tikhonov

Zhorov

2008

Journal of Biological Chemistry

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In our open channel model, key functional groups of BTZs interact with BTZ-sensing residues, which were identified in previous mutational experiments. The bulky tricyclic moiety occupies interface between domains III and IV, while the ammonium group protrudes into the inner pore, where it is stabilized by nucleophilic C-ends of the pore helices. In the closed channel model, contacts with several ligand-sensing residues in the inner helices are lost, which weakens ligand-channel interactions. An important feature of the ligand-binding mode in both open and closed channels is an interaction between the BTZ carbonyl group and a Ca 2؉ ion chelated by the selectivity filter glutamates in domains III and IV. In the absence of Ca 2؉ , the tricyclic BTZ moiety remains in the domain interface, while the ammonium group directly interacts with a glutamate residue in the selectivity filter. Our model suggests that the Ca 2؉ potentiation involves a direct electrostatic interaction between a Ca 2؉ ion and the ligand rather than an allosteric mechanism. Energy profiles indicate that BTZs can reach the binding site from the domain interface, whereas access through the open activation gate is unlikely, because reorientation of the bulky molecule in the pore is hindered. Benz(othi)azepines (BTZs)2 represent one of three main classes of ligands of L-type calcium channels (1, 2). Tonic (resting) block of Ca 2ϩ channels is usually measured by applying infrequent depolarization stimuli. Frequency-dependent block is measured during more rapid trains of depolarization stimuli. Increasing the stimulation frequency generally leads to more effective inhibition by BTZs (3-5). Voltage and activation dependence of the block are consistent with the idea that different functional states of the channel have different affinities for the drug in the order inactivated Ͼ open Ͼ closed state. These observations are consistent with the "modulated receptor" hypothesis (6), which was initially proposed to explain the action of local anesthetics on Na ϩ channels. The effect of BTZs also depends on the ionic environment. Raising concentrations of Ca 2ϩ or Ba 2ϩ antagonize diltiazem block (3). However, the block is more pronounced when Ca 2ϩ rather than Ba 2ϩ is used as a charge carrier (3, 7), and thus the block is considered potentiated by Ca 2ϩ (7). The conductance with Ba 2ϩ is higher than with Ca 2ϩ , because Ca 2ϩ binds more tightly to the outer-pore glutamates (8). These experiments suggest that the high affinity binding of BTZs requires a cation binding in the channel.Extracellular applications of both the tertiary and quaternary BTZ analogs effectively block Ca 2ϩ channels. In contrast, intracellular application of the same compounds does not result in significant block, leading to the conclusion that BTZs block the channels via an extracellular pathway (9 -11).Mutational studies have largely delimited BTZ-sensing residues to the inner helices and P-loops of domains III and IV (see Table 1). However, applying experimental data for mapping the BTZ...

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“…Although widely used in therapy, the compound has a relatively short duration of action. In the search for superior compounds, Floyd et al (21) substituted the benzazepinone ring structure for the benzothiazepinone of diltiazem. Metabolism studies on this class of compound showed that the principal routes of metabolism were similar to that for diltiazem with N-demethylation, conversion to an aldehyde, (pre-cursor of an acid), deacetylation and N-demethylation all occurring.…”

Section: Conjugation and Compound Structurementioning

confidence: 99%

Design of drugs through a consideration of drug metabolism and pharmacokinetics

Smith

1994

Eur. J. Drug Metab. Pharmacokinet.

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Drug metabolism input to the discovery process has been to date largely on an empirical case by case basis. Considerable advances have been made, such that basic rules can be applied to the behaviour of a compound in man based on physico-chemistry and structure. This is particularly true in the area of the cytochrome P-450 enzymes, the principal enzymes involved in the primary clearance of drugs. The major human forms, CYP2D6, CYP2C9 and CYP3A4 all have distinct substrate preferences which are being catalogued and rationalised. Such understandings will not only impact on existing drugs. Since the enzymes and systems will remain the same, these understandings can be applied to the design of molecules for the targets of the future, whilst the structure activity relationships of those targets are being researched and revealed.

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Benzazepinone calcium channel blockers. 2. Structure activity and drug metabolism studies leading to potent antihypertensive agents. Comparison with benzothiazepinones

Cited by 67 publications

References 1 publication

Identification of the Atypical L-Type Ca²⁺ Channel Blocker Diltiazem and Its Metabolites As Ghrelin Receptor Agonists

Identification of the Atypical L-Type Ca²⁺ Channel Blocker Diltiazem and Its Metabolites As Ghrelin Receptor Agonists

Molecular Modeling of Benzothiazepine Binding in the L-type Calcium Channel

Design of drugs through a consideration of drug metabolism and pharmacokinetics

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Benzazepinone calcium channel blockers. 2. Structure activity and drug metabolism studies leading to potent antihypertensive agents. Comparison with benzothiazepinones

Cited by 67 publications

References 1 publication

Identification of the Atypical L-Type Ca2+ Channel Blocker Diltiazem and Its Metabolites As Ghrelin Receptor Agonists

Identification of the Atypical L-Type Ca2+ Channel Blocker Diltiazem and Its Metabolites As Ghrelin Receptor Agonists

Molecular Modeling of Benzothiazepine Binding in the L-type Calcium Channel

Design of drugs through a consideration of drug metabolism and pharmacokinetics

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Identification of the Atypical L-Type Ca²⁺ Channel Blocker Diltiazem and Its Metabolites As Ghrelin Receptor Agonists

Identification of the Atypical L-Type Ca²⁺ Channel Blocker Diltiazem and Its Metabolites As Ghrelin Receptor Agonists