Synthesis and characterization of an affinity label for brain receptors to psychotomimetic benzomorphans: differentiation of σ-type and phencyclidine receptors

Adams, Joanne T.; Teal, P; Sonders, Mark S.; Tester, Barbara C.; Esherick, Joseph S.; Scherz, Michael W.; Keana, John F. W.; Weber, Eckard

doi:10.1016/0014-2999(87)90654-6

Cited by 14 publications

(6 citation statements)

References 10 publications

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“…DTG is inactive at PCP receptors (Weber et al, 1986;Manallack et al, unpublished observations), and its potency at D2 receptors would appear to be negligible from our results. Indeed, it was demonstrated recently that a DTG analogue with high selectivity for the areceptor was inactive at the D2 receptor (Adams et al, 1987). Considerable evidence from radioreceptor (Zukin and Zukin, 1979;Quirion et al, 1981;Su, 1981Su, , 1982Tam, 1983Tam, , 1985Vignon et al, 1983;Largent et al, 1984Largent et al, , 1986Largent et al, , 1987Martinet al, 1984;Tam and Cook, 1984;Gundlach et al, 1985;Contreras et al, 1986;Weber et al, 1986;Wong et al, 1986), autoradiographic (Quirion et al, 198 1 ;Sircar and Zukin, 1985;Gundlach et al, 1986;Largent et al, 1986;McLean and Weber, 1988), and quantitative structure-activity relationship Manallack and k a r t , 1987;Van de Waterbeemd et al, 1987; studies exists demonstrating the distinction of a-receptors and PCP receptors.…”

Section: Subchronic Administration Of Rimcazole Significantlymentioning

confidence: 99%

Regulation of σ‐Receptors: High‐ and Low‐Affinity Agonist States, GTP Shifts, and Up‐Regulation by Rimcazole and 1,3‐Di(2‐Tolyl)guanidine

Beart

O'Shea

Manallack

1989

Journal of Neurochemistry

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The regulation of the central sigma-binding site was investigated using both in vitro and in vivo manipulations in conjunction with radioligand binding. The displacement of the binding of R(+)-[3H]3-[3-hydroxyphenyl]-N-(1-propyl)piperidine [R(+)-[3H]3-PPP] to cortical homogenates by a range of drugs was consistent with the site labelled being a sigma-receptor. (+)-SKF 10,047, (-)-SKF 10,047, (+/-)-cyclazocine, phencyclidine, and dexoxadrol displaced R(+)-[3H]3-PPP with pseudo-Hill coefficients of less than 1. Further analysis employing nonlinear curve fitting techniques demonstrated that displacement data for these compounds were described better by a model whereby R(+)-[3H]3-PPP was displaced from two discrete sites; approximately 65% of the total sites were in the high-affinity state. In the presence of 10 mM Mg2+ and 0.3 mM GTP, displacement curves for (+)-SKF 10,047 and (+/-)-cyclazocine were shifted to the right. These findings were due to the shift of some 15% of the high-affinity binding sites to a low-affinity state. Saturation experiments revealed that 0.3 mM GTP acted competitively to decrease the affinity of R(+)-[3H]3-PPP for the sigma sites. The sigma-binding site was thus likely to be linked to a guanine nucleotide regulatory (G) protein. Thus sigma drugs could be subdivided on the basis of their GTP sensitivity and pseudo-Hill coefficients, and by analogy with other receptors R(+)-3-PPP, (+)-SKF 10,047, and (+/-)-cyclazocine, may be putative sigma-agonists. 1,3-Di(2-tolyl)guanidine (DTG), rimcazole, and haloperidol displaced R(+)-[3H]3-PPP with pseudo-Hill coefficients of approximately unity and thus may be sigma-antagonists. Subchronic treatment with rimcazole was characterized by slight sedation and a concomitant up-regulation, with a decrease in the affinity, of sigma-binding sites. The schedule of rimcazole also increased dopamine turnover in the nucleus accumbens; both the concentration of 3,4-dihydroxyphenylacetic acid (DOPAC) and the DOPAC/dopamine ratio were elevated. DTG produced similar alterations to the binding parameters of the sigma-binding site; however, changes were not observed in general behavior or accumbal dopamine turnover. sigma-Receptors are likely to be linked to a G protein and are functionally involved in the CNS.

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Section: Subchronic Administration Of Rimcazole Significantlymentioning

confidence: 99%

Regulation of σ‐Receptors: High‐ and Low‐Affinity Agonist States, GTP Shifts, and Up‐Regulation by Rimcazole and 1,3‐Di(2‐Tolyl)guanidine

Beart

O'Shea

Manallack

1989

Journal of Neurochemistry

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“…Adams et al . found that di- o -tolylguanidine isothiocyanate (DIGIT) was an irreversible inhibitor at σ receptors. They suggested that DIGIT may acylate or form covalent bonds with amino groups of the σ binding protein.…”

Section: Resultsmentioning

confidence: 99%

“…It is not able to acylate the σ sites, but it may simply partition in the lipid environment, producing high local concentrations of ligand, or it may acylate a nucleophile at a site adjacent to the σ 1 receptor. Adams et al 12 found that di-o-tolylguanidine isothiocyanate (DIGIT) was an irreversible inhibitor at σ receptors. They suggested that DIGIT may acylate or form covalent bonds with amino groups of the σ binding protein.…”

Section: Resultsmentioning

confidence: 99%

“…This effect is selective for the σ site because binding of ligands for PCP, dopamine D 2 , benzodiazepine, and μ-opioid receptors is unaffected. However there are no data for benzomorphan ligands .…”

Section: Introductionmentioning

confidence: 99%

“…However there are no data for benzomorphan ligands. 12 Metaphit had different effects on the binding of various radiolabeled σ ligands. 13 The order of sensitivity to metaphit was [ 3 H]-DTG > [ 3 H]-(+)-3PPP .…”

Section: Introductionmentioning

confidence: 99%

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Synthesis of (+)-cis-N-(4-Isothiocyanatobenzyl)-N-normetazocine, an Isothiocyanate Derivative of N-Benzylnormetazocine as Acylant Agent for the σ₁ Receptor

et al. 2002

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(+)-cis-N-(4-Isothiocyanatobenzyl)-N-normetazocine (BNIT) (+)-(4) was designed and synthesized as a derivative of the potent and selective sigma(1) receptor ligand (+)-cis-N-benzyl-N-normetazocine for irreversibly blocking sigma(1) binding sites. Pretreatment of guinea pig brain membranes with BNIT (0.1, 1, and 5 microM) caused a concentration-dependent loss of binding of the selective sigma(1) ligand [(3)H]-(+)-pentazocine. Binding experiments with [(3)H]-1,3-di(2-tolyl)guanidine ([(3)H]-DTG), a ligand of sigma(1) and sigma(2) receptors, showed that pretreatment with BNIT blocked only the sigma(1) component of [(3)H]-DTG binding.

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Synthesis of high specific activity tritium labelled 1S,2S‐(‐)‐trans‐2‐isothiocyanato‐N‐methyl‐N‐[2‐(1‐pyrrolidinyl)‐cyclohexyl]benzeneacetamide, a specific irreversible ligand for kappa opioid receptors

Costa

Thurkauf

Rothman

et al. 1990

Labelled Comp Radiopharmac

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Optically pure tritium labeled lS,2S-(-)-trans-2-isothiocyanato-Nmethyl-N-[2-(l-pyrrolidinyl)cyclohexyl]benzeneacetamide, an affinity ligand specific for the kappa opioid receptor was synthesized from optically pure 1 S,2S-(-)-trans-2-amino-N-methyl-N-[2-( 1pyrrolidinyl)cyclohexyl]benzeneacetamide via the sequence of dibromination (57%) followed by catalytic tritiation of the dibromide. The resulting tritium labelled aniline (14% yield, specific activity 31.2 Ci/mmol) was transformed to the title compound in 13.3% yield and 99+% radiochemical purity by treatment with thiophosgene.

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Synthesis and characterization of an affinity label for brain receptors to psychotomimetic benzomorphans: differentiation of σ-type and phencyclidine receptors

Cited by 14 publications

References 10 publications

Regulation of σ‐Receptors: High‐ and Low‐Affinity Agonist States, GTP Shifts, and Up‐Regulation by Rimcazole and 1,3‐Di(2‐Tolyl)guanidine

Regulation of σ‐Receptors: High‐ and Low‐Affinity Agonist States, GTP Shifts, and Up‐Regulation by Rimcazole and 1,3‐Di(2‐Tolyl)guanidine

Synthesis of (+)-cis-N-(4-Isothiocyanatobenzyl)-N-normetazocine, an Isothiocyanate Derivative of N-Benzylnormetazocine as Acylant Agent for the σ₁ Receptor

Synthesis of high specific activity tritium labelled 1S,2S‐(‐)‐trans‐2‐isothiocyanato‐N‐methyl‐N‐[2‐(1‐pyrrolidinyl)‐cyclohexyl]benzeneacetamide, a specific irreversible ligand for kappa opioid receptors

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Synthesis and characterization of an affinity label for brain receptors to psychotomimetic benzomorphans: differentiation of σ-type and phencyclidine receptors

Cited by 14 publications

References 10 publications

Regulation of σ‐Receptors: High‐ and Low‐Affinity Agonist States, GTP Shifts, and Up‐Regulation by Rimcazole and 1,3‐Di(2‐Tolyl)guanidine

Regulation of σ‐Receptors: High‐ and Low‐Affinity Agonist States, GTP Shifts, and Up‐Regulation by Rimcazole and 1,3‐Di(2‐Tolyl)guanidine

Synthesis of (+)-cis-N-(4-Isothiocyanatobenzyl)-N-normetazocine, an Isothiocyanate Derivative of N-Benzylnormetazocine as Acylant Agent for the σ1 Receptor

Synthesis of high specific activity tritium labelled 1S,2S‐(‐)‐trans‐2‐isothiocyanato‐N‐methyl‐N‐[2‐(1‐pyrrolidinyl)‐cyclohexyl]benzeneacetamide, a specific irreversible ligand for kappa opioid receptors

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Product

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Synthesis of (+)-cis-N-(4-Isothiocyanatobenzyl)-N-normetazocine, an Isothiocyanate Derivative of N-Benzylnormetazocine as Acylant Agent for the σ₁ Receptor