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J D McKenney

Publications and source records attributed to J D McKenney.

10 recordsLinked to original sources
PubMed1988

Stimulus generalization of 1-(3-trifluoromethylphenyl)piperazine (TFMPP) to propranolol, pindolol, and mesulergine.

Using standard operant procedures with rats trained to discriminate the serotonin (5-HT) agonist 1-(3-trifluoromethylphenyl)piperazine (TFMPP) (0.5 mg/kg) from saline, tests of stimulus generalization and stimulus antagonism were conducted with propranolol, pindolol, and mesulergine. Neither propranolol nor mesulergine antagonized the TFMPP stimulus (pindolol was not evaluated as an antagonist). However, TFMPP-stimulus generalization occurred with all three agents. These results suggest that the TFMPP-stimulus may involve both a 5-HT1B and a 5-HT1C mechanism and further suggest that propranolol, pindolol, and mesulergine may be capable of acting as agonists at certain populations of serotonin receptors.

Adrenergic beta-Antagonists↗
PubMed1986

TFMPP may produce its stimulus effects via a 5-HT1B mechanism.

Tests of stimulus generalization were conducted using rats trained to discriminate 1.0 mg/kg of 1-(3-trifluoromethylphenyl)piperazine (TFMPP) from saline in a standard two-lever operant procedure. Generalization of the TFMPP-stimulus was found to occur with fenfluramine and 1-(3-chlorophenyl)-piperazine (mCPP); generalization did not occur with 8-OH DPAT, quipazine, LSD, 5-OMe DMT or 2,5-DMA. Furthermore, the TFMPP-stimulus was not antagonized by pretreatment of the animals with tetrahydrotrazodone (THT). Based on the results of these studies, and on the results of previous binding studies with these same agents, it is suggested that the stimulus properties of TFMPP are mediated primarily via a 5-HT1B mechanism.

Animals↗
PubMed1986

5-HT1 and 5-HT2 binding characteristics of 1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane analogues.

1-(2,5-Dimethoxy-4-bromophenyl)-2-aminopropane (DOB; 1a) is a purported serotonin (5-HT) agonist that binds selectively to central 5-HT2 binding sites. Systematic removal of any or all of the aromatic substituents had relatively little effect on 5-HT1 binding but reduced 5-HT2 binding by approximately 2 or more orders of magnitude. Demethylation of the 2-methoxy group of 1a, or introduction of an N-n-propyl group, doubled 5-HT1-site affinity but decreased 5-HT2-site affinity by 3- and 30-fold, respectively. In tests of stimulus generalization, using rats trained to discriminate DOM from saline, the 2-demethyl and N-propyl derivatives were found to produce stimulus effects similar to those of DOB. In addition, the S-(+) isomer of the iodo analogue of 1a was found to possess one-third the affinity of its R-(-) enantiomer at 5-HT2 sites and also resulted in DOM-stimulus generalization. Of the DOB analogues examined, DOB (1a) possesses optimal selectivity for 5-HT2 binding.

Animals↗
PubMed1986

Synthesis and evaluation of phenyl- and benzoylpiperazines as potential serotonergic agents.

The binding of a series of phenylpiperazines (3) and benzoylpiperazines (4) to central serotonin (5-HT) sites was investigated. Several derivatives of 3 displayed nanomolar affinities for 5-HT1 sites, whereas derivatives of 4 were essentially inactive both at 5-HT1 and 5-HT2 sites. 1-(2-Methoxyphenyl)piperazine (2-MPP, 3a) was found to possess an affinity (Ki = 35 nM) for 5-HT1 sites comparable to that of the recognized 5-HT agonist 1-[3-(trifluoromethyl)phenyl]piperazine (TFMPP) (Ki = 20 nM); 3a also displayed a 100-fold selectivity for 5-HT1 sites (as compared to 8-fold for TFMPP). In tests of stimulus generalization using rats trained to discriminate TFMPP (ED50 = 0.17 mg/kg) from saline, 3a was found to be nearly equipotent (ED50 = 0.22 mg/kg) with the training drug. These results suggest that 3a may be a novel and more selective 5-HT1 agonist than TFMPP.

Animals↗
PubMed1986

5-HT1 and 5-HT2 binding characteristics of some quipazine analogues.

Arylpiperazines, such as 1-(3-trifluoromethylphenyl)piperazine (TFMPP) and its chloro analogue mCPP, are 5-HT1 agonists, whereas quipazine, i.e., 2-(1-piperazino)quinoline, appears to be a 5-HT2 agonist. Radioligand binding studies using rat cortical membrane homogenates and drug discrimination studies using rats trained to discriminate a 5-HT1 agonist (i.e., TFMPP) or a 5-HT2 agonist (i.e., 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM)) from saline reveal that quipazine and its 1-deaza analogue 2-naphthylpiperazine (2-NP) bind at 5-HT1 and 5-HT2 sites but produce stimulus effects similar to those of DOM. A structurally related compound, 1-naphthylpiperazine (1-NP), possesses a high affinity for 5-HT1 (Ki = 5 nM) and 5-HT2 (Ki = 18 nM) sites. 1-NP produces stimulus effects similar to those of TFMPP and is able to antagonize the stimulus effects produced by DOM. The present results suggest that the unsubstituted benzene ring of quipazine, and of its 1-deaza analogue 2-naphthylpiperazine, makes a significant contribution to the binding of these agents to 5-HT2 sites and, more importantly, may account for their 5-HT2 agonist properties.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1984

Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents.

The affinities (Ki values) of twenty two psycho-active agents, including LSD, 5-OMe DMT and a series of phenalkylamine derivatives, for cortical 5-HT1 and 5-HT2 binding sites were compared with two measures of behavioral activity. It was found that a significant correlation (r = 0.938) exists between the 5-HT2 binding affinities of these agents and their ED50 values as determined in tests of stimulus generalization using 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) as the training drug. Furthermore, for fifteen of these agents where human data were available, a significant correlation (r = 0.924) also exists between 5-HT2 binding affinities and their human hallucinogenic potencies. The results of this study suggest that the mechanism of action of these agents involves 5-HT2-related events.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1984

Discriminative stimulus properties of the serotonin agonist 1-(3-trifluoromethylphenyl)piperazine (TFMPP).

Using a standard two-lever drug discrimination procedure, twelve rats were trained to discriminate 1.0 mg/kg of the serotonin (5-HT) agonist TFMPP from saline. Once trained, the animals displayed a dose-related decrease in discriminative performance upon administration of lower doses of TFMPP. Tests of stimulus generalization were performed using the purported 5-HT agonist RU-24, 969 and 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM). While TFMPP produced stimulus effects similar to those of RU-24,969, these effects seem to be dissimilar to those of DOM. The results of the present study suggest that the discriminative stimulus effects of TFMPP may involve a 5-HT1-related mechanism.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1984

Structure-activity studies on amphetamine analogs using drug discrimination methodology.

Animals (rats) trained to discriminate 1.0 mg/kg of S(+)-amphetamine sulfate from saline, using a standard operant training procedure, were administered doses of various amphetamine analogs in tests of stimulus generalization in order to study structure-activity relationships (SAR). The types of structural variation of the amphetamine molecule that were investigated included (a) benz-fusion of the aromatic nucleus, (b) alpha-demethylation of the alkyl side chain, (c) conversion of the benzylic methylene to a carbonyl group, and (d) conformational restriction of the side chain. Benz-fusion and alpha-demethylation appear to have a detrimental effect on activity in that none of these analogs produced amphetamine-appropriate responding. However, the carbonylated analog, i.e., cathinone, was found to be equipotent with amphetamine. Furthermore, as with amphetamine, the S-isomer of cathinone was found to be more active than its enantiomer. With respect to the conformationally-restricted analogs, the most potent compound was 2-aminotetralin which was about half as active as racemic amphetamine.

Alkaloids↗
PubMed1984

Synthesis and evaluation of a novel series of N,N-dimethylisotryptamines.

A novel series of N,N-dimethylisotryptamine (isoDMT) derivatives, i.e., derivatives of 1-[2-(dimethylamino)ethyl]indole, was prepared and found to be isosteric with their corresponding N,N-dimethyltryptamine (DMT) counterparts with respect to serotonin receptor (rat fundus) affinity. Whereas the isoDMT derivatives possessed a greater affinity than did their corresponding DMT derivatives, they were relatively ineffective in displacing [3H]-5-HT binding from rat brain (cortex) homogenates. In a drug discrimination paradigm, using rats as subjects, 6-OMe-isoDMT produced effects similar to those of 5-OMe-DMT. Attempts to antagonize the discriminative stimulus effects of the hallucinogen 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) using two of the isoDMT derivatives proved unsuccessful.

Animals↗