title: The effects of sigma ligands on protein release from lacrimal acinar cells: a potential agonist/antagonist assay.
abstract: Sigma receptor antagonists have been proposed as leading clinical candidates for use in various psychotic disorders. Prior to clinical testing, it is imperative that a new agent be correctly identified as an antagonist and not an agonist since the latter may worsen the psychosis. For sigma-ligands many behavioral and pharmacological assays have been developed in an attempt to classify agonist/antagonist activity. These assays evaluate a response or a behavior in an animal model that can be related to clinical efficacy. However, is the action by the presumed antagonist a consequence of sigma-receptor activity? Previously we have identified sigma-receptors in acinar cells of the main lacrimal gland of the New Zealand white rabbit and have measured protein release after the addition of various N,N-disubstituted phenylalkylamine derivatives known to be sigma-ligands by receptor binding studies. Although protein release from acinar cells has been attributed to either muscarinic or alpha-adrenergic stimulation, protein release from sigma-receptor stimulation was also confirmed. In the reported studies here, we isolated and incubated acinar cells with varying concentrations of known sigma-ligands and measured protein concentration. A knowledge of the receptor profile for the disubstituted phenylalkylamines permitted experiments to be designed in which various alpha, muscarinic, serotonergic, and dopaminergic antagonists could be added in equimolar concentrations. Under the conditions of these experiments, statistically significant increases in protein release for sigma-ligands could be attributed to stimulation of sigma-receptors. Haloperidol, an apparent sigma-antagonist, caused a statistically significant decrease in protein release and also inhibited protein release when tested with a known sigma-ligand, AF2975 [N,N-dimethyl-2-phenylethylamine]. In this system, stimulation and inhibition of protein release were defined as agonist and antagonist behavior, respectively. Of particular interest were the results for BMY14802 and +/- pentazocine, both of which were found to be agonists. Various antipsychotic and antidepressant drugs were measured for their agonist/antagonist behavior. Because of multireceptors present in acini, their agonist or antagonist behaviour could not be attributed solely to interaction with the sigma-receptor unless specific antagonists were added.
authors.affiliation: Division of Pharmaceutics, University of Iowa, College of Pharmacy, Iowa City 52242, USA.
authors.forename: R D
authors.initials: RD
authors.lastname: Schoenwald
authors.forename: C F
authors.initials: CF
authors.lastname: Barfknecht
authors.forename: S
authors.initials: S
authors.lastname: Shirolkar
authors.forename: E
authors.initials: E
authors.lastname: Xia
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000494:pharmacology; D005136:Eye Proteins / Q000378:metabolism*; D006146:Guanidines / Q000378:metabolism / Q000494:pharmacology; D006220:Haloperidol / Q000378:metabolism / Q000494:pharmacology; D066298:In Vitro Techniques; D007765:Lacrimal Apparatus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010423:Pentazocine / Q000494:pharmacology; D010627:Phenethylamines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011817:Rabbits; D017480:Receptors, sigma / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D005136:Eye Proteins; D006146:Guanidines; D010627:Phenethylamines; D011743:Pyrimidines; D017480:Receptors, sigma; C042434:tear proteins; C050408:alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol; C043554:N,N-dimethylphenylethylamine; D006220:Haloperidol; C050232:1,3-ditolylguanidine; D010423:Pentazocine