Antagonism of a (+)N-allylnormetazocine stimulus by (-)PPAP and several structurally related analogs.
Employing rats trained to discriminate 5 mg/kg of the benzomorphan opioid (+)N-allylnormetazocine [(+)NANM] from vehicle, tests of stimulus generalization and antagonism were conducted to determine the influence of several potential sigma-receptor ligands. It has been previously suggested that the (+)NANM stimulus may involve concurrent action at sigma- and phencyclidine (PCP) receptors. Although the low-affinity sigma-antagonist rimcazole was without stimulus-attenuating effect, three novel sigma-ligands--(-)PPAP, CNS 3018, and CNS 3093 (ID50 doses = 3.2, 6.7, and 4.5 mg/kg, respectively)--antagonized the (+)NANM stimulus in a dose-related fashion. The nonselective serotonergic agent 1-(3-trifluoromethyl)phenylpiperazine (TFMPP) produced partial generalization in (+)NANM-trained animals whereas buspirone, a 5-hydroxytryptamine1A (5-HT1A) agonist, attenuated (to 27% drug-appropriate responding) the (+)NANM stimulus. Because the prototypic 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) failed to attenuate the (+)NANM stimulus at pharmacologically relevant doses, it seems unlikely that the (+)NANM stimulus involves a 5-HT1A mechanism. TFMPP and buspirone display modest affinity for sigma-receptors and this may account for the present findings with these agents. The present results neither establish a role for sigma involvement in the stimulus properties of (+)NANM nor eliminate a role for PCP receptors. They do, however, demonstrate that sigma-ligands with little to no affinity for PCP receptors are capable of antagonizing the (+)NANM stimulus.
Glennon
R A
RA
Department of Medicinal Chemistry, School of Pharmacy, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0540.
Young
R
R
Herndon
J L
JL
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000588:Amines / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D002065:Buspirone / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology; D005795:Generalization, Stimulus / Q000187:drug effects; D008297:Male; D010620:Phenazocine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010636:Phenols / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011437:Propylamines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017478:Receptors, Phencyclidine / Q000187:drug effects; D017480:Receptors, sigma / Q000187:drug effects; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
D000588:Amines; D014150:Antipsychotic Agents; D002227:Carbazoles; D010636:Phenols; D010879:Piperazines; D011437:Propylamines; D017478:Receptors, Phencyclidine; D017480:Receptors, sigma; D017366:Serotonin Receptor Agonists; C068473:N-(3-phenyl-n-propyl)-1-phenyl-2-aminopropane; C083392:N-(3-phenyl-n-propyl)-1-(4-hydroxyphenyl)-2-aminopropane; C083393:N-cyclohexylmethyl-N-(5-phenylpentyl)amine; C018406:1-(3-trifluoromethylphenyl)piperazine; C012134:SK&F 10047; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C034931:rimcazole; D010620:Phenazocine; D002065:Buspirone