Recent in vitro receptor binding studies have indicated that indole-2-carboxylates with halogen substitutions at the position 5 or 6 are potent competitive antagonists of the NMDA (N-methyl-D-aspartate)-associated strychnine-insensitive glycine receptor (Gray N. M., Dappen M. S., Cheng B. K., Cordi A. A., Biesterfeldt J. P., Hood W. F. and Monahan J. B. (1992) J. med. Chem. 34: 1283-1292; Hood W. F., Gray N. M., Dappen M. S., Watson G. B., Compton R. P., Cordi A. A., Larthorn T. H. and Monahan J. B. (1992) J. Pharmac. exp. Ther. 262: 654-660). In the present investigation, a series of indole-2-carboxylates and two putative antagonists of glycine receptor HA-966 (3-amino-l-hydroxypyrrolidin-2-one) and 7-chlorokynurenic acid were examined for their effects on cGMP responses, mediated by the NMDA receptor complex, in vivo. Both SC-49648 (6-chloro-2-carboxyindole-3-acetic acid, intracerebellar injection, i.c.b.) and HA-966 (i.c.b. or intraperitoneal, i.p.) antagonized increases in levels of cyclic GMP in the cerebellum of the mouse, induced by the intracerebellar administration of NMDA and D-serine, agonists of the NMDA and the NMDA-associated glycine recognition sites, respectively. The drugs SC-49648 and 7-chlorokynurenic acid (i.p.) did not affect cGMP responses, suggesting poor bioavailability in brain. Following direct intracerebellar injection, SC-49648 was eliminated with a half-life of 12 min from the brain. Following intraperitoneal administration, SC-50132, the 3-ethylester analog of SC-49648, was eliminated from the brain with a half-life of 35 min and was found to be metabolized to SC-49648, in vivo. Some lipophilic analogs of SC-49648, designed as its prodrugs, were minimally active as glycine antagonists, in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

We have synthesized a series of indole-2-carboxylate derivatives and, with the use of radioligand binding, electrophysiological techniques and an in vivo transient bilateral carotid occlusion model of ischemic damage known to be sensitive to NMDA antagonists, have evaluated the indole-2-carboxylate derivatives ability to inhibit N-methyl-D-aspartate (NMDA) receptor activity through the associated glycine modulatory site. By using [3H]glycine to label this modulatory site, we found that the compounds with the highest affinity (Ki less than 1 microM) contained a chloro group at position C-6 and a polar, hydrogen-bond-accepting group at position C-3 of the indole ring. When these compounds were tested for their ability to modulate [3H]MK-801 [(+)-[3H]-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclophepten-5,10- imine maleate) binding, a functional assessment of NMDA receptor activation, binding was inhibited, indicative of NMDA receptor antagonist character. Schild regression analysis indicated that this antagonism was competitive with glycine. Next, several of these indole-2-carboxylate derivatives were analyzed electrophysiologically in rat cortex mRNA-injected Xenopus oocytes shown to express a functional NMDA receptor channel complex. These compounds inhibited NMDA receptor activity in a manner noncompetitive with NMDA. They also produced a parallel right-ward shift in the glycine dose response for potentiation of the NMDA responses in the oocytes and thus provided further evidence for a competitive interaction at the glycine site. Finally, in vivo transient bilateral carotid artery occlusion experiments revealed that these compounds were capable of reducing the damage typically associated with an ischemic insult in Mongolian gerbil hippocampal neurons.

U-50,488H, a kappa (kappa) opioid ligand with moderate potency at sigma (sigma) receptors, protects against mechanical and ischemia-induced injury. The purpose of this study was to evaluate the possibility that sigma-receptors may be involved in mediating the neuroprotective actions of U-50,488H. This possibility was examined by testing the potential of a series of U-50,488H analogs, which are potent sigma-ligands with minimal activity at kappa-opioid receptors, to protect against ischemia-induced neuronal damage in the gerbil. Like U-50,488H, BD-449 (20 mg/kg), the cis-diastereomer of U-50,4888H, protected against ischemia-induced neuronal damage as did BD-737 (50 and 30 mg/kg) and BD-738 (50 mg/kg). All 3 compounds interacted selectively with sigma-receptors. In contrast, BD-601 (50 mg/kg), did not protect against ischemia-induced neuronal damage, although it also interacted potently with sigma-receptors. One difference between the compounds that were neuroprotective and BD-601 is that only BD-601 produced sigma-like behavioral effects in the rat. Thus, it is possible that BD-601 may interact differently or at a different sigma-subtype than BD-449, BD-737 and BD-738 with sigma-receptors. However, these results clearly indicate that an interaction with kappa-opioid receptors is not required for anti-ischemic activity, and that sigma-receptors may play a role in neuroprotection.

In the present investigation, the effects of sigma ligands [WY-47384 [8-fluoro-2,3,4,5-tetrahydro-2[3-(3-pyridinyl)propyl)1H- pyrido(4,3b)indole], (+)-pentazocine, (+)-SFK 10,047 (N-allylnormetazocine), mafoprazine, opipramol, dextromethorphan, dextrorphan, (+)-3-PPP [3-(3-hydroxyphenyl)-N-propylpiperidine], (-)-butaclamol, DTG [1,3-di(2-tolyl)guanidine], rimcazole, ifenprodil and BMY-14802 [alpha-(fluorophenyl)-4-(5-fluoropyrimidinyl)-1-piperazine butanol]] on harmaline-, pentylenetetrazol (PTZ)-, methamphetamine (MA)- and D-serine-induced increases in mouse cerebellar levels of cGMP were determined. Ifenprodil, BMY-14802, dextromethorphan, dextrorphan, (+)-SKF 10,047, opipramol and mafoprazine reversed harmaline-, PTZ-, MA- and D-serine-induced increases in levels of cGMP. Rimcazole reversed only the harmaline-induced response. WY-47384 reversed harmaline-, MA-, D-serine-, but not PTZ- or quisqualate-induced increases in levels of cGMP. (+)-Pentazocine attenuated harmaline- and D-serine-, but not PTZ- and MA-induced cGMP responses. Haloperidol did not affect harmaline- and D-serine-induced cGMP responses. (+)-3-PPP and (-)-butaclamol did not affect any of the responses studied. Furthermore, (+)-3-PPP-induced increases in levels of cGMP were reversed by the competitive N-methyl-D-aspartate (NMDA) antagonist, CPP]3-(2-carboxypiperazin-4-yl)propyl- 1-phosphonic acid, the non-competitive NMDA antagonist, (+)-MK-801 (dizocilipine maleate), the NMDA-associated glycine receptor antagonist, HA-966 (3-amino-1-hydroxypyrrolidin-2-one), the partial glycine agonist, DCS (D-cycloserine) as well as by the sigma ligands, ifenprodil, WY-47384, (+)-pentazocine, (+)-SKF 10,047, dextromethorphan and dextrorphan but not by rimcazole.(ABSTRACT TRUNCATED AT 250 WORDS)

A series of indole-2-carboxylates were prepared and evaluated for their ability to inhibit the binding at the strychnine-insensitive glycine receptor that is associated with the NMDA-PCP-glycine receptor complex. All of the compounds were selective for the glycine site relative to other sites on the receptor macrocomplex and several of the compounds in this series were found to have submicromolar affinity for this receptor. The lead compound, 2-carboxy-6-chloro-3-indoleacetic acid (Ki = 1.6 microM vs [3H]glycine), was also found to noncompetitively inhibit the binding of MK-801, a ligand for the phencyclidine site on the receptor macrocomplex. These latter data suggest that the compound functions as an antagonist at the strychnine-insensitive glycine receptor. The structural activity relationships within this series of indole-2-carboxylates is discussed and several key pharmacophores are identified for this series of glycine ligands. In general, the most potent compounds were the C-3 acetamides, with N-propyl-2-carboxy-6-chloro-3-indoleacetamide having the highest receptor affinity.

The effects of sigma ligands, (+)3PPP 3-[3-hydroxyphenyl-N(1-propyl) piperidine] and (-)butaclamol, were evaluated in vivo on the metabolism of dopamine (DA) and in the striatum release of adrenocorticotrophic hormone (ACTH) and prolactin in the rat and changes in levels of cyclic guanosine monophosphate (cGMP) in the cerebellum of the mouse and compared with the effects of (+)NANM (N-allyl-normetazocine, SKF 10,047) and (+)pentazocine. Both (+)3PPP and (-) butaclamol decreased the release of prolactin and did not affect the metabolism of DA. N-Allyl-normetazocine and (+)pentazocine increased release of prolactin and have been shown previously to increase the metabolism of DA. All four ligands increased release of ACTH; however, only the increases caused by (+)NANM and (+)pentazocine were reversed by pretreatment with CPP, a N-methyl-D-aspartate (NMDA) receptor antagonist. (+)Pentazocine and (+)NANM inhibited the NMDA receptor-mediated changes in levels of cGMP in the cerebellum of the mouse, while (+)3PPP and (-)butaclamol did not attenuate the response to NMDA. In addition to further confirming a functional interaction between sigma receptors and NMDA receptors, these studies divide the observed effects of putative sigma ligands into two groups, characterized by benzomorphan compounds and non-benzomorphan compounds, suggesting the possibility of subtypes at sigma receptor in vivo.

Certain benzeneacetamides [(-)- and (+)-cis-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]benzeneacetamide] were recently reported to be potent sigma receptor ligands. In order to determine whether efficacy for the sigma receptor could be improved, a series of compounds related to the benzeneacetamides, N-substituted cis-2-(1-pyrrolidinyl)-N-methylcyclohexylamines, were synthesized and their structure-activity requirements were determined. The compounds were synthesized by starting with the previously reported (+/-)-, 1S,2R-(+)-, and 1R,2S-(-)-cis-2-(1-pyrrolidinyl)-N-methylcyclohexylamines. Analysis of sigma ([3H](+)-3-PPP), kappa ([3H]bremazocine and [3H]U69,593), dopamine-d2 ([3H](-)-sulpiride), and phencyclidine (PCP) ([3H]TCP) receptor binding in guinea pig brain revealed a number of highly potent and selective sigma receptor ligands. Notably, 1S,2R-cis-(-)-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-(2-naphthyl) acetamide [(-)-29] (Ki = 8.66 +/- 0.35 nM), (+/-)-cis-2-amino-4,5-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl] benzeneacetamide [(+/-)-17] (Ki = 11 +/- 3 nM), 1S,2R-(-)-cis-N-methyl-N-[2-(3,4-dichlorophenyl)ethyl]-2-(1-pyrrolidinyl ) cyclohexylamine [(-)-44] (Ki = 1.3 +/- 0.3 nM), and 1R,2S-(+)-cis-N-methyl-N-[2-(3,4-dichlorophenyl)ethyl]-2-(1-pyrrolidinyl ) cyclohexylamine. [(+)-44] (Ki = 6 +/- 3 nM) exhibited very high affinity at sigma receptors, by displacement of [3H]-(+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [( 3H]-(+)-3-PPP). These compounds showed insignificant affinity for kappa, dopamine, or PCP receptors, making them valuable tools for the study of sigma receptors. Furthermore, these compounds also exhibited enantioselectivity ranging from 5-fold for (+)- and (-)-44 to 160-fold for (+)- and (-)-29. Several other compounds showed equivalent selectivity but displayed lower sigma receptor affinity.

Several antihistamines were evaluated for their ability to interact with sigma, muscarinic and histaminic H1 binding sites in rat brain preparations. All of the antihistamines were able to interact with the sigma site, as well as the other two sites. In addition, tripelennamine was found to elicit sigma-like behaviors when administered to rats. This affinity for the sigma site suggests that the compounds may elicit some of their undesirable CNS side effects via this interaction.

SL 82.0715 and ifenprodil are potent anti-ischemic agents, which are believed to be due to non-competitive antagonism of N-methyl-D-aspartate (NMDA). It has been proposed that SL 82.0715 and ifenprodil non-competitively antagonize the actions of NMDA by interacting as antagonists with a polyamine site associated with the NMDA/phencyclidine (PCP)/glycine complex. The present study demonstrates that the actions of SL 82.0715 and ifenprodil may also be due in part to an interaction with sigma binding sites, a property that is not shared with polyamines.

A series of 1,2,3,4-tetrahydroisoquinolines, tetrahydrothieno[2,3-c]pyridines, and related compounds were evaluated for their ability to inhibit binding of [3H]-1-[1-(2-thienyl)piperidine and [3H]-N-allylnormetazocine to phencyclidine (PCP) and sigma receptors, respectively. A representative series of compounds was evaluated in behavioral assays to determine the ability of the compounds to induce PCP-like stereotyped behavior and ataxia. All of the compounds caused stereotyped behavior and ataxia, indicating their agonist actions at the PCP site.

Antihistamines are effective medications that have been used for decades in the management of allergic rhinitis; however, they may be administered or selected in an inappropriate fashion and may be the source of drug-related morbidity. Our objective is to present relevant background information and an expert consensus statement on the use of antihistamines in treatment of allergic rhinitis. In July 2002, 14 experts in allergy, clinical immunology, pharmacology, and impairment assessment were invited to participate in a roundtable conference to present current concepts and develop a consensus statement on the clinical management of allergic rhinitis with antihistamines. Many of the antihistamines used to treat allergic rhinitis, as well as the disease itself, may produce sedation, impairment, and reduced quality of life. Allergic rhinitis is more appropriately managed with the relatively nonimpairing second-generation antihistamines (eg, loratadine, desloratadine, cetirizine, and fexofenadine), because older agents (eg, diphenhydramine, chlorpheniramine, and brompheniramine) produce sedation and impairment and worsen sleep architecture. Although there is some debate surrounding the varying degrees of efficacy of second-generation antihistamines, it is known that some agents may produce varying levels of drowsiness or impairment, especially at higher than recommended doses. The differences with regard to safety among the second-generation antihistamines are smaller than are the differences between the first and second generations. A nonsedating, nonimpairing (even at higher than recommended doses), second-generation antihistamine is preferred for all patients, particularly those with a higher risk for the development of adverse effects. We recommend that primary care and specialist physicians, nurse practitioners, physician assistants, pharmacists, and all other health professionals involved in the diagnosis and treatment of allergic rhinitis follow this consensus document and share this information with patients for whom antihistamine therapy is recommended. In addition, further epidemiologic studies on the effects of antihistamines should be performed. (J Allergy Clin Immunol 2003;111:S835-42.)

Phenycyclidine (PCP) produces many profound effects in the central nervous system. PCP has numerous behavioral and neurochemical effects such as inhibiting the uptake and facilitating the release of dopamine, serotonin, and norepinephrine. PCP also interacts with sigma, mu opioid, muscarinic, and nicotinic receptors. However, the psychotomimetic effects induced by PCP are believed to be mediated by specific PCP receptors, where PCP binds with greater potency than sigma compounds. Electrophysiological, behavioral, and neuro-chemical evidence strongly suggests that at least some of the many PCP actions result from antagonism of excitatory amino acid-induced responses via PCP receptors. The recent isolation and partial characterization of the alpha and beta endopsychosins and the identification of other endogenous ligands for the PCP and sigma receptors, is another promising area of research in the elucidation of the physiological role of an endogenous PCP and sigma system.