Effects of sigma receptor ligands on schedule-controlled behavior of rats: relation to sigma and PCP receptor binding affinity

Abstract

Eleven drugs were examined for their ability to inhibit sigma and phencyclidine (PCP) receptor binding, as labelled by (+)[3H]-R-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3-PPP), [3H]ditolylguanidine (DTG), (+)[3H]N-allylnormetazocine (NANM) and [3H]1-(1-(2-thienyl)cyclohexyl)piperidine (TCP), in membrane preparations from whole rat brain. The same drugs were studied for their effects under a fixed-ratio (FR) schedule of food reinforcement in rats. The relative potency order of the drugs for decreasing FR responding was: haloperidol greater than (+)-3-PPP greater than (-)NANM greater than BMY 14802 greater than PCP greater than (+)NANM greater than DTG greater than rimcazole greater than JO 1783 greater than JO1784 greater than (-)butaclamol. The binding affinities of all 11 drugs for either the [3H]DTG, (+)[3H]-3-PPP, (+)[3H]NANM or [3H]TCP site did not correlate significantly with the potencies of the same drugs for decreasing FR behavior. Rimcazole, (+)-3-PPP and haloperidol, at behaviorally inactive doses, were studied for their effects as antagonists of the rate-decreasing effects of JO 1784, DTG and (+)NANM: rimcazole attenuated the effects of DTG and (+)NANM but not JO 1784; (+)-3-PPP attenuated the effects of (+)NANM but not JO 1784 and DTG; and haloperidol was devoid of antagonistic actions. Moreover, BMY 14802 did not attenuate the rate-decreasing effects of (+)-3-PPP. These results further indicate that it is difficult to distinguish between purported sigma agonist and antagonist drugs.

Repeated administration of Sigma ligands alters the population activity of rat midbrain dopaminergic neurons

“…DTG itself is toxic so that caution must be exercised in the interpretation of highdose effects of this compound . JO 1784, although not a benzomorphan, also shows a specific sigma binding profile and appears to show selectivity for the sigma, site (Roman et al, 1990;Wettstein et al, 1991).…”

Sigma ligands, but not N-methyl-D-aspartate antagonists, reduce levodopa-induced dyskinesias

“…Although perplexing, this pattern is consistent with several past studies that demonstrated blockade of dopamine agonist-induced behavioral effects by σ ligands. Separate groups have independently concluded that their results did not correlate with known σ classification schemas [22,23]. Thus, it is possible that dextromethorphan may be a partial σ-1 agonist, for example.…”

3,4-Dihydro-2(1H)-quinolinone as a Novel Antidepressant Drug: Synthesis and Pharmacology of 1-[3-[4-(3-Chlorophenyl)-1-piperazinyl]propyl]-3,4- dihydro-5-methoxy-2(1H)-quinolinone and Its Derivatives

“…First, we examined the effects of the length of the alkyl chain, positional change of the chloro substituent, introduction of another chlorine substituent at the 5-position, and replacement of the chloro substituent with a variety of substituents in 34b. Change of the side chain from propyl to ethyl (36) and butyl (37), positional change in the chloro substituent from 3 to 2 and 4 (38,39), and introduction of another chlorine substituent to the 5-position (40) resulted in the inactive compounds. Replacement of the chlorine substituent in the 3-chlorophenyl-1-piperazinyl moiety in 34 with a more bulky bromine substituent (42) hand, replacement of the chlorine substituent with a smaller fluorine substituent (41), with electron-donating methyl (44), hydroxy (45), and methoxy (46) groups, and with a nitrile group (47), which has greater electronwithdrawing nature but less lipophilicity than a chloro group, gave inactive compounds.…”

“…This test has been reported as the experimental model for cerebral trauma, and the central nervous system activator pyroglutamylhistydylprolineamide tartarate (TRH-T, 65) 38 and its γ-butyrolactone γ-carbonyl analogue 39 show promotional effects in this test. Binding affinities to σ receptors for all prepared compounds were evaluated by their abilities to inhibit the binding of [ 3 H]-1,3-di(o-tolyl)guanidine ([ 3 H]DTG) to rat whole brain membranes 40 (Table 3). The clinically available central nervous system activator 65, the classical tricyclic antidepressant 1, the putative σ receptor agonists 1,3-di(o-tolyl)guanidine (DTG, 66), (+)-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(2-propenyl)-2,6-methano-3-benzazecin-8-ol (SKF10,047, 67), and (+)-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(3-methyl-2butenyl)-2,6-methano-3-benzazecin-8-ol (pentazocine, 68), and the putative σ receptor antagonists R-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinebutanol hydrochloride (BMY14802, 69) and cis-9- [3-(3,5-dimethyl-1-piperazinyl)propyl]carbazole dihydrochloride (rimcazole, 70) were also examined in the two tests as reference drugs.…”

“…Preparation of a membrane fraction and a [ 3 H]-1,3-di(o-tolyl)guanidine binding test were performed according to the reported method. 40 Preparation of a membrane fraction: A Wistar strain male rat was decapitated and the whole brain was excised and homogenized in 30 volumes of an ice-cooled Tris buffer. The homogenate was then centrifuged at 4 °C and 50000g for 15 min to give the first sediment, which was suspended in 1 volume of the buffer.…”