RESUMEN
2,2,6,6-Tetramethylpiperidine-1-oxyl-4-amino-4-carboxylic acid (TOAC) is a topographically and conformationally restricted, nitroxide containing, C(alpha)-tetrasubstituted alpha-amino acid. Here, we describe the molecular and crystal structures, as determined by X-ray diffraction analyses, of a TOAC terminally protected derivative, the cyclic dipeptide c(TOAC)(2).1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) solvate, and five TOAC-containing, terminally protected, linear peptides ranging in length from tetra- to hepta-peptides. Incipient and fully developed, regular or distorted 3(10)-helical structures are formed by the linear peptides. A detailed discussion on the average geometry and preferred conformation for the TOAC piperidine ring is also reported. The X-ray diffraction structure of an intramolecularly cyclized side product resulting from a C-activated TOAC residue has also been determined.
Asunto(s)
Cristalografía por Rayos X , Óxidos N-Cíclicos/química , Péptidos/química , Conformación Proteica , Marcadores de SpinRESUMEN
Biphalin is a dimeric opioid peptide, composed of two tetrapeptides connected 'tail-to-tail', that exhibits a high affinity for all three opioid receptor types (i.e. mu, delta and kappa). This study presents the X-ray crystal structure of biphalin sulfate and compares it to other opioids that interact with the same biological targets. Both halves of the molecule have a folded backbone conformation but differ significantly from one another. Residues 1-4 in biphalin, which compare well with the delta selective opioid peptide DADLE, fold into a random coil. Residues 5-8, which can be fit to the mu selective peptide D-TIPP-NH2, exhibit a fairly normal type III' beta bend. Biphalin also exhibits structural similarities with two naltrexone analogs, naltrexonazine and norbinaltorphamine, that are specific to mu and kappa receptor sites.
Asunto(s)
Encefalinas/química , Naltrexona/análogos & derivados , Tetrahidroisoquinolinas , Sitios de Unión , Cristalografía por Rayos X , Leucina Encefalina-2-Alanina/química , Encefalinas/síntesis química , Enlace de Hidrógeno , Naltrexona/química , Narcóticos/química , Oligopéptidos/química , Docilidad , Conformación Proteica , Pliegue de Proteína , Receptores Opioides delta/química , Receptores Opioides kappa/química , Receptores Opioides mu/química , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
We have prepared azabicyclo[3.2.1] derivatives (C-3-substituted tropanes) that bind with high affinity to the dopamine transporter and inhibit dopamine reuptake. Within the series, 3-[2-[bis-(4-fluorophenyl)methoxy]ethylidene]-8-methyl-8-azabicyclo[3.2.1]octane (8) was found to have the highest affinity and selectivity for the dopamine transporter. These azabicyclo[3.2.1] (bridged piperidine) series of compounds differ from the well-known benztropines by a 2-carbon spacer between C-3 and a diarylmethoxy moiety. Interestingly, these new compounds demonstrated a much lower affinity for the muscarinic-1 site, at least a 100-fold decrease compared to benztropine. Replacing N-methyl with N-phenylpropyl in two of the compounds resulted in a 3-10-fold increase in binding affinity for the dopamine transporter. However, those compounds lost selectivity for the dopamine transporter over the serotonin transporter. Replacement of the ether oxygen in the diarylmethoxy moiety with a nitrogen atom gave relatively inactive amines, indicating the important role which is played by the ether oxygen in transporter binding. Reduction of the C-3 double bond in 8 gave 3 alpha-substituted tropanes, as shown by X-ray crystallographic analyses of 11, 12, and 19. The 3 alpha-substituted tropanes had lower affinity and less selectivity than the comparable unsaturated ligands.
Asunto(s)
Inhibidores de Captación de Dopamina/síntesis química , Dopamina/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Proteínas del Tejido Nervioso , Piperazinas/química , Tropanos/síntesis química , Animales , Encéfalo/metabolismo , Proteínas Portadoras/metabolismo , Cristalografía por Rayos X , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Inhibidores de Captación de Dopamina/química , Inhibidores de Captación de Dopamina/metabolismo , Técnicas In Vitro , Masculino , Glicoproteínas de Membrana/metabolismo , Ratas , Ratas Sprague-Dawley , Receptor Muscarínico M1 , Receptores Muscarínicos/metabolismo , Serotonina/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática , Relación Estructura-Actividad , Tropanos/química , Tropanos/metabolismoRESUMEN
With the goal of developing potential Alzheimer's pharmacotherapeutics, we have synthesized a series of novel analogues of the potent anticholinesterases phenserine (2) and physostigmine (1). These derivatives contain methyl (3, 4, 6), dimethyl (5, 7, 8, 10, 11) and trimethyl (14) substituents in each position of the phenyl group of the phenylcarbamoyl moieties, and with N-methyl and 6-methyl substituents (12, 13, 31, 33). We also quantified the inhibitory action of these compounds against human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). An analysis of the structure/anticholinesterase activity relationship of the described compounds, together with molecular modeling, confirmed the catalytic triad mechanism of the binding of this class of carabamate analogues within AChE and BChE and defined structural requirements for their differential inhibition.
Asunto(s)
Acetilcolinesterasa/metabolismo , Butirilcolinesterasa/metabolismo , Carbamatos/síntesis química , Inhibidores de la Colinesterasa/síntesis química , Fisostigmina/análogos & derivados , Fisostigmina/síntesis química , Carbamatos/química , Carbamatos/farmacología , Inhibidores de la Colinesterasa/química , Cristalografía por Rayos X , Eritrocitos/química , Humanos , Modelos Moleculares , Conformación Molecular , Fisostigmina/química , Relación Estructura-ActividadRESUMEN
Ions of structure X[N(O)NO]-, examples of which have seen increasing use as probes for studying the biology of nitric oxide (NO) over the past decade, have a varied chemical history spanning nearly two centuries. Nevertheless, they have not been widely appreciated for their physicochemical similarities. Here we begin a series of systematic inquiries into the fundamental chemistry of such compounds aimed at identifying both the characteristics that justify considering them as a group and the factors that contribute to observed differences in their physicochemical properties. In the present paper, X-ray structures in which X is SO3- (1), O- (2), Ph (3), and Et2N (5), as well as that of the gem-disubstituted carbon derivative CH2[N(O)NO]2-(2) (4), are compared. All their O-N-N-O systems are essentially planar, with cis oxygens and an N-N linkage exhibiting considerable double-bond character. The ultraviolet spectrum of the isolated chromophore consists of a relatively intense ( approximately 6-10 mM(-1) x cm(-1) per [N(O)NO]- group) absorption at 248-250 nm (for 2 and 5) that is red shifted by through-space Stark interactions (e.g., by approximately 10 nm in 1 and 4) as well as by conjugative interaction with X (lambda(max) = 284 nm for 3). Infrared and Raman spectra for the widely used pharmacological probe 5 were determined, with analysis of vibrational modes being aided by comparison with the spectra of the [15N(O)15NO]- isotopomer and density functional theory calculations at the B3LYP/6-311++G** level. To address confusion that has arisen in the literature resulting from rather widespread use of differing trivial designations for this class of compounds, a unifying nomenclature system is recommended in which compounds containing the [N(O)NO]- moiety are named as diazeniumdiolates. It is hoped that these and other efforts to understand and predict the physicochemical similarities and differences among different members of the diazeniumdiolate class will aid in reaping their full potential in the area of rational drug design.
Asunto(s)
Aniones/química , Óxido Nítrico/química , Fenómenos Químicos , Química Física , Cristalografía por Rayos X , Técnicas de Sonda Molecular , Óxido Nítrico/metabolismo , Espectrofotometría Infrarroja , Espectrofotometría Ultravioleta , Terminología como AsuntoRESUMEN
Novel piperidine-based bivalent ligands were prepared in enantiomerically pure form and evaluated for their ability to inhibit reuptake of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) into rat brain nerve endings (synaptosomes). In this study, we have succeeded in using (1) the length of the linking chain connecting the two piperidine-based monomer units and (2) the absolute configuration of the piperidine monomer as a means to tailor activity and selectivity at the three monoamine transporters tested. In this series, the bivalent ligand 16, comprised of two (+)-trans-piperidine units linked by a pentamethylene spacer, exhibits a combination of high DA transporter (DAT) and 5-HT transporter (SERT) activity (K(i) = 39 nM and 7 nM, respectively). Piperidine 16 is capable of reducing cocaine's locomotor effects in mice while not having any effect on locomotion when tested alone. Additionally, compound 16 (1-10 mg/kg) does not substitute for cocaine in drug discrimination studies in rats. However, the analogous bivalent ligand 15 comprised of two (-)-trans-piperidine units, which is SERT selective, was less effective in antagonizing cocaine's locomotor stimulant activity. The piperidine-based bivalent inhibitors described herein constitute a new class of monoamine reuptake inhibitors that exhibit varying levels of monoamine transporter activity and selectivity, and these ligands may serve as lead candidates in the discovery of new therapeutics to treat a range of neurological disorders including cocaine addiction.
Asunto(s)
Proteínas de Transporte de Membrana , Proteínas del Tejido Nervioso , Inhibidores de la Captación de Neurotransmisores/síntesis química , Piperidinas/síntesis química , Simportadores , Animales , Proteínas Portadoras/metabolismo , Cocaína/farmacología , Cristalografía por Rayos X , Aprendizaje Discriminativo/efectos de los fármacos , Dopamina/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Ligandos , Masculino , Glicoproteínas de Membrana/metabolismo , Ratones , Actividad Motora/efectos de los fármacos , Inhibidores de la Captación de Neurotransmisores/química , Inhibidores de la Captación de Neurotransmisores/farmacología , Norepinefrina/metabolismo , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática , Piperidinas/química , Piperidinas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Serotonina/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática , Estereoisomerismo , Conducta Estereotipada/efectos de los fármacos , Relación Estructura-Actividad , Sinaptosomas/metabolismoRESUMEN
Ions of structure R(2)N[N(O)NO](-) and their alkylation products have seen increasing use as nitric oxide (NO)-generating agents for biomedical research applications. Here we show that such diazeniumdiolate anions can readily displace halide from a variety of electrophilic aza- or nitroaromatic substrates to form O(2)-arylated derivatives of structure R(2)N-N(O)=N-OAr. The site of arylation and the cis arrangement of the oxygens were confirmed by X-ray crystallography. Displacement by various nucleophiles showed R(2)N[N(O)NO](-) to be a reasonably good leaving group, with rate constants for displacement by hydroxide, methoxide, and isopropylamine that were between those of chloride and fluoride in the S(N)Ar reactions we surveyed. The Meisenheimer intermediate could be spectrally observed. These O(2)-aryl diazeniumdiolates proved capable of reacting with the nucleophilic sulfur of the HIV-1 p7 nucleocapsid protein's zinc finger assembly to eject the zinc, disrupting a structural motif critical to viral replication and suggesting possible utility in the drug discovery realm.
Asunto(s)
Aminas/química , Aniones/síntesis química , Fármacos Anti-VIH/síntesis química , Imidas/síntesis química , Óxido Nítrico/química , Células Cultivadas , Fenómenos Químicos , Química Física , Cristalografía por Rayos X , Cinética , Espectrometría de Fluorescencia , Linfocitos T/efectos de los fármacos , Linfocitos T/virología , Dedos de ZincRESUMEN
A study of the effect of transposition of the internal nitrogen atom for the adjacent benzylic carbon atom in delta-selective agonists such as BW373U86 (1) and SNC-80 (2) has been undertaken. It was shown that high-affinity, fully efficacious, and delta opioid receptor-selective compounds can be obtained from this transposition. In addition to the N,N-diethylamido group needed as the delta address, the structural features identified to promote delta receptor affinity in the set of compounds studied included a cis relative stereochemistry between the 3- and 4-substituents in the piperidine ring, a trans-crotyl or allyl substituent on the basic nitrogen, the lack of a 2-methyl group in the piperidine ring, and either no substitution or hydroxyl substitution in the aryl ring not substituted with the N,N-diethylamido group. Structural features found to be important for mu affinity include hydroxyl substitution in the aryl ring, the presence of a 2-methyl group in a cis relative relationship to the 4-amino group as well as N-substituents such as cyclopropylmethyl. It was also determined that mu receptor affinity could be increased while maintaining delta receptor affinity, especially when hydroxyl-substituted compounds are considered. Additionally, it was discovered that the somewhat lower mu/delta selectivities observed for the piperidine compounds relative to the piperazine-based ligands appear to arise as a consequence of the carbon-nitrogen transposition which imparts an overall lower delta and higher mu affinity to the piperidine-based ligands. This higher affinity for the mu receptor, apparently intrinsic to the piperidine-based compounds, suggests that ligands of this class will more easily be converted to mu/delta combination agonists compared to the piperazine ligands such as 1. This is particularly important since analogues of 1, which show both mu- and delta-type activity, are now recognized as important for their strong analgesia and cross-canceling of many of the side effects found in agonists operating exclusively from either the delta or mu opioid receptor.
Asunto(s)
Benzamidas/química , Piperazinas/química , Piperidinas/química , Receptores Opioides delta/metabolismo , Animales , Benzamidas/metabolismo , Encéfalo/metabolismo , Cristalografía por Rayos X , Cobayas , Técnicas In Vitro , Ligandos , Piperazinas/metabolismo , Piperidinas/metabolismo , Ensayo de Unión Radioligante , Ratas , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of methoxy-containing derivatives of indatraline 13a-f and 17 were synthesized, and their binding affinities for the dopamine, serotonin, and norepinephrine transporter binding sites were determined. Introduction of a methoxy group to indatraline affected its affinity and selectivity greatly. Except for the 4-methoxy derivative 13a,which had the same high affinity at the dopamine transporter binding site as indatraline, the other methoxy-containing analogues (13b-f and 17) exhibited lower affinity than indatraline for the three transporter binding sites. However, some of the analogues were more selective than indatraline, and the 6-methoxy derivative 13c displayed the highest affinity for both the serotonin and norepinephrine transporters. This compound retained reasonable affinity for the dopamine transporter and is a promising template for the development of a long-acting inhibitor of monoamine transporters. Such inhibitors have potential as medications for treatment, as a substitution medication, or for prevention of the abuse of methamphetamine-like stimulants.
Asunto(s)
Proteínas Portadoras/metabolismo , Dopamina/metabolismo , Indanos/síntesis química , Glicoproteínas de Membrana/metabolismo , Proteínas de Transporte de Membrana , Metilaminas/síntesis química , Proteínas del Tejido Nervioso , Inhibidores de la Captación de Neurotransmisores/síntesis química , Norepinefrina/metabolismo , Serotonina/metabolismo , Simportadores , Animales , Unión Competitiva , Cristalografía por Rayos X , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Diseño de Fármacos , Indanos/química , Indanos/metabolismo , Metilaminas/química , Metilaminas/metabolismo , Inhibidores de la Captación de Neurotransmisores/química , Inhibidores de la Captación de Neurotransmisores/metabolismo , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática , Ensayo de Unión Radioligante , Proteínas de Transporte de Serotonina en la Membrana Plasmática , Relación Estructura-ActividadRESUMEN
The synthesis and monoamine transporter activity of additional members of a series of 3,4-disubstituted piperidines (truncated analogues of the WIN series) are described. All members of this series were prepared from arecoline hydrobromide in optically pure form and were evaluated for their ability to inhibit high affinity uptake of dopamine (DA), serotonin (5-HT) and norepinephrine (NE) into rat brain nerve endings (synaptosomes). Most of the compounds prepared in this series are reasonably potent DAT inhibitors (K(i) values of 4-400 nM) and have selectivity for the 5-HT transporter relative to both the NE transporter (3-9-fold) and to the DAT ( approximately 25-fold). In the present series, (-)-methyl 1-methyl-4beta-(2-naphthyl)piperidine-3beta-carboxylate (6) was found to be the most potent piperidine-based ligand, exhibiting K(i)'s of 21 nM and 7.6 nM at the DAT and 5-HTT, respectively. While the 5-HTT activity of compound 6 is comparable to that of the antidepressant medication fluoxetine, it is less selective. As is apparent from the data presented, the naphthyl substituted piperidines 6-9, which differ in their stereochemistry, show different degrees of selectivity for the three transporters. Consistent with results reported in the literature for the tropane analogues, removal of the methyl group from the nitrogen atom of 9 leads to a further enhancement in 5-HTT activity. To examine the in vivo effects of these piperidines, preliminary behavioral screening was carried out on piperidine 14. Despite its 2.5-fold greater DAT activity compared to cocaine, piperidine 14 was found to be about 2. 5-fold less potent in increasing distance traveled in mice. However, consistent with its DAT activity, piperidine 14 was found to be about 2.5-fold more potent than cocaine in enhancing stereotypic movements. Further studies of these piperidine-based ligands may provide valuable insights into the pharmacological mechanisms underlying the enhancement in distance traveled versus stereotypic movements. The present results have important implications for better understanding the structural motifs required in the design of agents with specific potency and selectivity at monoamine transporters.
Asunto(s)
Cocaína/química , Inhibidores de Captación de Dopamina/síntesis química , Proteínas de Transporte de Membrana , Proteínas del Tejido Nervioso , Piperidinas/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Animales , Encéfalo/metabolismo , Proteínas Portadoras/antagonistas & inhibidores , Dopamina/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Inhibidores de Captación de Dopamina/química , Inhibidores de Captación de Dopamina/farmacología , Técnicas In Vitro , Masculino , Glicoproteínas de Membrana/antagonistas & inhibidores , Ratones , Modelos Moleculares , Actividad Motora/efectos de los fármacos , Terminaciones Nerviosas/metabolismo , Norepinefrina/metabolismo , Piperidinas/química , Piperidinas/farmacología , Ratas , Serotonina/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática , Inhibidores Selectivos de la Recaptación de Serotonina/química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Estereoisomerismo , Conducta Estereotipada/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Trichogin GA IV is a 11-residue lipopeptaibol antibiotic exhibiting membrane modifying properties. We synthesized step-by-step by solution methods three trichogin analogues, each with a double Aib (alpha-aminoisobutyric acid)-->TOAC (2,2,6,6-tetramethylpiperidine-1-oxyl-4-amino-4-carboxylic acid) replacement. The strict similarity in the conformational propensities of Aib and TOAC allowed us to exploit these analogues in a detailed investigation of the conformation of this lipopeptaibol in different organic solvents and in a membrane-mimetic environment using in particular the double spin labeling ESR technique. We conclude that the secondary structure in solution remains essentially unchanged if compared to that previously found in the crystal state for trichogin. More specifically, the N-terminal region of the peptide folds in a 3(10)-helix, while the central and C-terminal regions are mainly alpha-helical. An additional, significant proof for the modest plasticity of the trichogin structure was obtained by an X-ray diffraction analysis of the nOct-[TOAC4,8, Leu-OMe11] analogue. For the three analogues permeability measurements revealed membrane-modifying properties comparable to those of natural trichogin.
Asunto(s)
Antibacterianos/química , Estructura Secundaria de Proteína , Ácidos Aminoisobutíricos/química , Permeabilidad de la Membrana Celular/efectos de los fármacos , Óxidos N-Cíclicos/química , Espectroscopía de Resonancia por Spin del Electrón , Colorantes Fluorescentes/farmacocinética , Glicopéptidos , Enlace de Hidrógeno , Lipopéptidos , Liposomas/metabolismo , Modelos Moleculares , Péptidos/síntesis química , Conformación Proteica , Pliegue de Proteína , Espectroscopía Infrarroja por Transformada de Fourier , Difracción de Rayos XRESUMEN
The inhibition of radioligand binding and [35S]GTPgammaS functional assay data for N-methyl- and N-phenethyl-9beta-methyl-5-(3-hydroxyphenyl)morphans (5b and 5c) show that these compounds are pure antagonists at the micro, delta, and kappa opioid receptors. Since 5b and 5c have the 5-(3-hydroxyphenyl) group locked in a conformation comparable to an equatorial group of a piperidine chair conformation, this information provides very strong evidence that opioid antagonists can interact with opioid receptors in this conformation. In addition, it suggests that the trans-3, 4-dimethyl-4-(3-hydroxyphenyl)piperidine class of antagonist operates via a phenyl equatorial piperidine chair conformation. Importantly, the close relationship between the 4-(3-hydroxyphenyl)piperidines and 5-(3-hydroxyphenyl)morphan antagonists shows that the latter class of compound provides a rigid platform on which to build a novel series of opioid antagonists.
Asunto(s)
Morfinanos/síntesis química , Antagonistas de Narcóticos , Animales , Cristalografía por Rayos X , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Cobayas , Técnicas In Vitro , Conformación Molecular , Morfinanos/química , Morfinanos/metabolismo , Morfinanos/farmacología , Putamen/efectos de los fármacos , Putamen/metabolismo , Ensayo de Unión Radioligante , Ratas , Receptores Opioides/metabolismo , Receptores Opioides delta/antagonistas & inhibidores , Receptores Opioides delta/metabolismo , Receptores Opioides kappa/antagonistas & inhibidores , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/antagonistas & inhibidores , Receptores Opioides mu/metabolismo , Relación Estructura-ActividadRESUMEN
To discover agents that might be useful in the treatment of cocaine abuse, we have chosen to re-explore a class of molecules that was first reported by Clarke et al. in 1973 and that was and shown to lack locomotor stimulatory activity in mice. These compounds are piperidine-3-carboxylic acid esters bearing a 4-chlorophenyl group in position 4, and as such, these structures may be viewed as truncated versions of the WIN series compounds, i.e., they lack the two-carbon bridge of the tropanes. All members of this class were synthesized starting from arecoline hydrobromide and obtained in optically pure form through resolution methods using either (+)- or (-)-dibenzoyltartaric acid. Interestingly, we have found that these piperidines do, in fact, exhibit substantial affinity in both WIN 35, 428 binding at the dopamine transporter and in the inhibition of [3H]dopamine uptake. Of all of the compounds synthesized, the 3-n-propyl derivative (-)-9 was found to be the most potent with a binding affinity of 3 nM. This simple piperidine is thus 33-fold more potent than cocaine in binding affinity and 29-fold more potent in its inhibition of dopamine uptake. Although no efforts have presently been made to "optimize" binding affinity at the DAT, the substantive activity found for the n-propyl derivative (-)-9 is remarkable; the compound is only about 10-fold less active than the best of the high-affinity tropanes of the WIN series. As a further point of interest, it was found that the cis-disubstituted piperidine (-)-3 is only about 2-fold more potent than its trans isomer (+)-11. This result stands in sharp contrast to the data reported for the tropane series, for the epimerization of the substituent at C-2 from beta to alpha has been reported to result in a lowering of activity by 30-200-fold. This smaller spread in binding affinities for the piperidines may reflect the smaller size of these molecules relative to the tropanes, which allows both the cis and the trans isomers to adjust themselves to the binding site on the DAT. Our present demonstration that these piperidine structures do, in fact, possess significant DAT activity, taken together with their reported lack of locomotor activity, provides a compelling argument for exploring this class of molecules further in animal behavioral experiments. The present work thus broadens the scope of structures that may be considered as lead structures in the search for cocaine abuse medications.
Asunto(s)
Proteínas Portadoras/antagonistas & inhibidores , Inhibidores de Captación de Dopamina/farmacología , Glicoproteínas de Membrana , Proteínas de Transporte de Membrana , Proteínas del Tejido Nervioso , Piperidinas/farmacología , Tropanos/química , Animales , Unión Competitiva , Proteínas Portadoras/metabolismo , Cocaína/análogos & derivados , Cocaína/metabolismo , Cocaína/farmacología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Cuerpo Estriado/ultraestructura , Cristalografía por Rayos X , Dopamina/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Inhibidores de Captación de Dopamina/síntesis química , Inhibidores de Captación de Dopamina/química , Inhibidores de Captación de Dopamina/metabolismo , Técnicas In Vitro , Estructura Molecular , Piperidinas/síntesis química , Piperidinas/química , Piperidinas/metabolismo , Unión Proteica , Ratas , Estereoisomerismo , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismoRESUMEN
N-Methyl- and N-phenylethyl-(+/-)-1,2,3,4,4a,5,10,10a- octahydro-4a-(3-hydroxyphenyl)-10a-methyl-benzo[g]isoquinolines (4 and 5, respectively) were found to be pure opioid antagonists. These compounds were shown to share many of the characteristics identified with the N-methyl- and N-phenylethyl trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine (1 and 2, respectively) including N-substituent mediated potency and a lack of N-substituent mediated antagonism. These data suggest that compounds 4 and 5 and the N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines (1 and 2) may interact with opioid receptors similarly.
Asunto(s)
Isoquinolinas/síntesis química , Antagonistas de Narcóticos , Antagonistas de Narcóticos/síntesis química , Animales , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Cobayas , Isoquinolinas/farmacología , Antagonistas de Narcóticos/farmacología , Piperidinas/farmacología , Relación Estructura-ActividadRESUMEN
Crystals of the two dipeptide title compounds, Tyr-D-Tic, C19H20N2O4.1.5H2O, and Tyr-D-Tic-NH2, C19H21N3O3.H2O, were prepared by the sitting-drop method. Tyr-D-Tic is orthorhombic (P2(1)2(1)2(1)) and crystallizes as a zwitterion. The asymmetric unit contains two peptide molecules and three molecules of water. Tyr-D-Tic-NH2 crystals are monoclinic (P2(1)), the asymmetric unit containing one peptide molecule and one molecule of water. Despite some differences in packing, the conformation of the two dipeptides is almost identical (r.m.s. deviation for non-H atoms is approximately 0.18 A).
Asunto(s)
Isoquinolinas/química , Péptidos Opioides/química , Tetrahidroisoquinolinas , Tirosina/análogos & derivados , Cristalografía por Rayos X , Enlace de Hidrógeno , Conformación Proteica , Tirosina/químicaRESUMEN
A series of N-alkyl- and N,N-dialkyl-4-[alpha-[(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl] benzyl]-benzamides were synthesized and evaluated for binding affinities at mu, delta, and kappa opioid receptor subtypes. Several compounds (2e,f,h,i,m) strongly bound to the delta receptor with IC50 values in the nanomolar range. On the other hand, the binding affinities of these compounds for the mu and kappa receptors were in the micromolar or greater range indicating excellent delta opioid receptor subtype selectivities. In this series, two important structure-activity relationships were found for the delta receptor binding affinity. First, the spatial orientation of the alpha-benzylic position influenced the affinities with the alpha R derivatives 2a-n generally showing more than 10-fold greater affinity than the alpha S derivatives 3a-n. Second, the binding affinities were strongly influenced by the number of alkyl substituents on the amide nitrogen. N-Monoalkylbenzamide derivatives 2b-d showed lower affinity than N,N-dialkylbenzamide derivatives 2e-n, and the N-unsubstituted benzamide derivative 2a had the lowest affinity for the delta receptor in the series. The dramatic effect of the amide group substitution pattern on the binding affinity for the delta receptor strongly suggests that the amide function is an important structural element in the interaction of this series of compounds at the delta receptor. Selective compounds in this series were examined for binding affinity in cloned human mu and delta receptors. The results obtained generally paralleled those from the rat brain binding assay. Compounds 2e,f with potent delta binding affinities and high delta selectivities were shown to be delta agonists with high selectivity by studies in the guinea pig ileum (GPI) and mouse vas deferens (MVD) preparations. Compound 2f was the most selective compound in the rat brain and GPI/MVD assays with 1755- and 958-fold delta vs mu selectivity, respectively.
Asunto(s)
Benzamidas/síntesis química , Narcóticos/agonistas , Narcóticos/síntesis química , Piperazinas/síntesis química , Receptores Opioides delta/agonistas , Alquilación , Animales , Benzamidas/química , Benzamidas/farmacología , Encéfalo/metabolismo , Células CHO , Membrana Celular/metabolismo , Cricetinae , Cristalografía por Rayos X , Cobayas , Humanos , Cinética , Masculino , Ratones , Ratones Endogámicos ICR , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Narcóticos/química , Narcóticos/farmacología , Piperazinas/química , Piperazinas/farmacología , Ensayo de Unión Radioligante , Ratas , Receptores Opioides delta/metabolismo , Receptores Opioides mu/metabolismo , Relación Estructura-Actividad , Transfección , Conducto Deferente/efectos de los fármacos , Conducto Deferente/fisiologíaRESUMEN
Tyr-D-Tic-Phe-Phe-NH2 (D-TIPP), a linear tetrapeptide containing the conformationally restricted Tic residue (tetrahydroisoquinoline-3-carboxylic acid), is an opioid agonist which exhibits high affinity and selectivity for the mu-receptor. Its conformational features have been studied using a combination, a solid-state (X-ray) and modeling (molecular mechanics and Monte Carlo simulations) methods. The results of the X-ray study showed two distinct conformers for D-TIPP, with the main differences lying in the orientation of the Tyr side-chain and the presence of both D-Tic(+) and D-Tic(-) conformations for the D-Tic residue. The peptide backbone is folded and stabilized by the formation of one intramolecular hydrogen bond. The modeling results also indicated a folded backbone for the peptide and both cis and trans conformers for the D-Tic residue are found in the lowest-energy structures. Comparison of the X-ray and modeling results shows many similarities especially around the D-Tic residue.
Asunto(s)
Antagonistas de Narcóticos/química , Oligopéptidos/química , Conformación Proteica , Receptores Opioides mu/agonistas , Tetrahidroisoquinolinas , Cristalografía por Rayos X/métodos , Modelos Moleculares , Oligopéptidos/síntesis químicaRESUMEN
The highly selective delta (delta) opioid receptor agonist SNC 80 [(+)-4- [(alpha R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N ,N- diethylbenzamide, (+)-21] and novel optically pure derivatives were synthesized from the enantiomers of 1-allyl-trans-2,5-dimethylpiperazine (2). The piperazine (+/-)-2 was synthesized, and its enantiomers were obtained on a multigram scale in > 99% optical purity by optical resolution of the racemate with the camphoric acids. The absolute configuration of (+)-2 was determined to be 2S,5R by X-ray analysis of the salt with (+)-camphoric acid. Since the chirality of the starting material was known, and the relative configuration of compounds (-)-21, (-)-22, and (+)-23 were obtained by single-crystal X-ray analysis, the assignment of the absolute stereochemistry of the entire series could be made. Radioreceptor binding studies in rat brain preparations showed that methyl ethers (+)-21 (SNC 80) and (-)-25 exhibited strong selectivity for rat delta receptors with low nanomolar affinity to delta receptors and only micromolar affinity for rat mu (mu) opioid receptors. Compounds (-)-21, (-)-22, and (-)-23 showed micromolar affinities for delta opioid receptors. The unsubstituted derivative (+)-22 and the fluorinated derivative (-)-27 showed > 2659- and > 2105-fold delta/mu binding selectivity, respectively. The latter derivatives are the most selective ligands described in the new series. Studies with some of the compounds described in the isolated mouse vas deferens and guinea pig ileum bioassays revealed that all were agonists with different degrees of selectivity for the delta opioid receptor. These data show that (+)-21 and (+)-22 are potent delta receptor agonists and suggest that these compounds will be valuable tools for further study of the delta opioid receptor at the molecular level, including its function and role in analgesia and drug abuse.
Asunto(s)
Benzamidas/síntesis química , Benzamidas/metabolismo , Piperazinas/síntesis química , Piperazinas/metabolismo , Receptores Opioides delta/agonistas , Animales , Benzamidas/química , Benzamidas/farmacología , Unión Competitiva , Encéfalo/metabolismo , Cristalografía por Rayos X , Encefalina Ala(2)-MeFe(4)-Gli(5) , Leucina Encefalina-2-Alanina/metabolismo , Encefalinas/metabolismo , Cobayas , Íleon/metabolismo , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Conformación Molecular , Estructura Molecular , Contracción Muscular/efectos de los fármacos , Piperazinas/química , Piperazinas/farmacología , Ensayo de Unión Radioligante , Ratas , Receptores Opioides delta/metabolismo , Receptores Opioides mu/metabolismo , Estereoisomerismo , Conducto Deferente/metabolismoRESUMEN
The molecular and crystal structures of four peptides containing one L-Trp guest residue in Aib (alpha-aminoisobutyric acid or C alpha-methyl alanine) host oligopeptide chains have been determined by X-ray diffraction. The peptides are Z-Aib-L-Trp-Aib-OMe, Z-(Aib)2-L-Trp-Aib-OMe, Z-(Aib)3-L-Trp-Aib-OtBu and Boc-(Aib)3-L-Trp-Aib-OMe. Right-handed beta-turns and incipient and fully developed 3(10)-helices are formed in the crystal state by the tri-, tetra- and pentapeptides, respectively. The Trp residue is easily accommodated in these folded structures. The average geometry and preferred conformation for the Trp indolyl side chain are also discussed.