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Biomedical subjects

L L Martin

Publications and source records attributed to L L Martin.

At least 55 records · Page 3Linked to original sources
PubMed1987

Biochemical and pharmacological characterization of CGS 12066B, a selective serotonin-1B agonist.

CGS 12066B is a novel pyrroloquinoxaline with selectivity for the serotonin-1B (5HT1B) recognition site as assessed by binding, biochemical and electrophysiological studies. The compound had an IC50 value of 51 nM at the 5HT1B recognition site as determined using the binding of [3H]5HT in the presence of 1 microM spiperone. At the 5HT1A receptor the compound had an IC50 value of 876 nM, providing a 5HT1A/5HT1B ratio of 17 in contrast to the putative 5HT1B selective agent trifluoromethylphenylpiperazine (TFMPP) which had a corresponding ratio of 3.6. The compound had minimal affinity for alpha 1-, alpha 2- and beta-adrenoceptors and for dopamine D-1 and D-2 receptors. CGS 12066B, in contrast to TFMPP, which was inactive, was found to inhibit dorsal raphe cell firing with an ED50 value of 358 nmol/kg i.v. The corresponding values for the 5HT1A selective agonists 8-OH-DPAT and ipsapirone were 1.3 and 33 nmol/kg. CGS 12066B was also effective in decreasing rat brain 5-HTP concentrations and inhibiting in vitro 5HT release. The data obtained indicate that CGS 12066B is a reasonably active 5HT1B site agonist, which due to its selectivity as compared to compounds such as TFMPP, will be a useful tool for evaluating the physiological role of such receptors in the mammalian CNS.

5-Hydroxytryptophan↗
PubMed1986

Structural relationships in the inhibition of [3H]tryptamine binding to rat brain membranes in vitro by phenylalkylamines.

The ability of various phenylalkylamines to inhibit the binding of [3H]tryptamine to rat frontal/parietal cortical membranes was examined in vitro. Affinity for [3H]tryptamine binding sites improved as the alkyl side chain was extended to include four carbons or when a methoxy group was added at the para position of the ring. One compound, p-methoxyphenylpropylamine (IC50 = 3.6 nM), was as potent as unlabelled tryptamine as a displacing agent. Based on the unique structure-activity relationship obtained, it appears that [3H]tryptamine binding sites do not mediate the actions of phenethylamines on serotonin uptake or release.

Alkylation↗
PubMed1986

Adaptive changes in the 5-HT2 binding site after chronic administration of agonists and antagonists.

This study confirms and extends an earlier report that acute administration of the serotonin (5-HT) antagonist, mianserin, caused a marked decrease in the density of 5-HT2 binding sites in brain of the rat (Blackshear and Sanders-Bush, 1982). Using [3H]ketanserin, a selective ligand for the 5-HT2 site, the present study further investigated the mechanism of this effect. The effects of mianserin in vivo and in vitro were compared with those of trifluoromethylphenylpiperazine (TFPP), a directly acting 5-HT agonist. While TFPP, unlike mianserin, was not active in single doses, it caused a 58% decrease in the density of 5-HT2 sites after repeated doses. The adaptive change induced by chronic treatment with TFPP was qualitatively and quantitatively similar to that caused by chronic administration of mianserin. Furthermore, mianserin and TFPP had similar effects in vitro; preincubation of membranes from brain induced a concentration-dependent increase in the Kd value with no change in the Bmax value. Similar adaptive changes in 5-HT2 sites after administration of mianserin, a presumed 5-HT antagonist, and after TFPP, a presumed 5-HT agonist, suggests that adaptive mechanisms in the serotonergic system are different from those in other aminergic systems or that the drugs used to characterize 5-HT receptor systems need to be re-evaluated.

Animals↗
PubMed1986

Autoradiographic localization and pharmacology of unique [3H]tryptamine binding sites in rat brain.

The distribution and pharmacological specificity of [3H]tryptamine binding to coronal and horizontal sections of the rat brain were investigated with computer-assisted autoradiography. [3H]Tryptamine bound to brain regions with up to 58% specificity, as determined with 10 microM tryptamine as a displacer. The capacity (Bmax) of saturable [3H]tryptamine binding sites was greatest in the nucleus accumbens and claustrum (660-760 fmol mg protein-1), with intermediate binding site concentrations in hippocampus, septum, olfactory tubercle, frontal cortex, cingulate cortex and caudate-putamen. The phenylalkylamine, p-methoxyphenylpropylamine and the beta-carboline, harmaline, as well as 5-methyl-tryptamine, displaced [3H]tryptamine from each of these brain regions with a potency that approximated the 5-9 nM affinity (Kd) of [3H]tryptamine binding to each site. Only micromolar concentrations of serotonin displaced [3H]tryptamine, which did not bind to S1, S2, D1, D2 or alpha- or beta-adrenergic sites. The unique pharmacology and the regional overlap of [3H]tryptamine binding sites with dopaminergic nerve terminals in the nucleus accumbens and caudate-putamen suggest that tryptamine-containing neurons in the mammalian brain may modulate behavioral functions such as locomotion.

Animals↗
PubMed1986

Person memory: the role of traits, group stereotypes, and specific behaviors in the cognitive representation of persons.

Subjects read a list of statements describing behaviors manifested by a target person who had previously been described by a set of personality trait adjectives. Some statements referred to the person by name, whereas others referred to him as a member of a stereotyped social group. The consistency of the behaviors with expectancies based on these general target characterizations was varied. Results of Experiment 1 showed that when the trait-adjective characterization of the target and the target's group membership had similar implications, the relative ease of recalling behaviors that were consistent and inconsistent with these implications depended on whether subjects had the opportunity to think more extensively about the information they received after all of it had been presented. Results of Experiment 2 showed that when a target's trait-adjective description and his group membership had dissimilar implications, subjects organized the person's behaviors around separate concepts, depending on whether the behavior statements referred to him by name or by group membership. Moreover, when subjects were told after they read the behaviors that the person described by trait adjectives was the same as the one referred to by group membership, they did not alter the cognitive representations they formed initially. These and other results suggested the existence of a priority system for engaging in goal-directed cognitive activity en route to forming a person impression, with lower priority activities giving way to higher priority ones when processing demands are high.

Cognition↗
PubMed1986

Set/reset: use and disuse of concepts in impression formation.

In three experiments, impressions of an ambiguously described stimulus person were assimilated toward the implications of primed concepts when performance of the priming task was interrupted, but were contrasted with these implications when performance of the priming task was allowed to continue to completion. In addition, when the primed concepts were evaluatively consistent (Experiment 1), assimilation and contrast were observed on both prime-related and prime-unrelated dimensions. When the primed concepts were evaluatively inconsistent (Experiment 2), however, these shifts in impression were observed only on dimensions directly related to the primed concepts. When no concepts descriptively relevant to the stimulus information were primed (Experiment 3), the assimilation and contrast were relative to the favorableness of a primed general evaluative person concept. Taken together, these results suggest that a concept may be accessible to an individual and may be relevant to target information, yet not be used to encode that information; that assimilation and contrast may occur for reasons other than the discrepancy between the target and the contextual stimuli on the dimension of judgment; and that individuals may use the evaluative implications of their person representation as a cue in deciding which of several equally applicable, equally accessible descriptive concepts to use in interpreting information about a person.

Adult↗
PubMed1985

Antagonism of L-5-hydroxytryptophan-induced head twitching in rats by lisuride: a mixed 5-hydroxytryptamine agonist-antagonist?

Lisuride antagonized L-5-hydroxytryptophan (5-HTP)-induced head twitches at doses lower than those sufficient to induce the serotonin (5-HT) syndrome. Among several other 5-HT agonists tested, only LSD and 1-(m-trifluoromethylphenyl)-piperazine (TFMPP) shared this paradoxical profile. Assessment of various dopamine (DA) agonists revealed a lack of correlation between DA-mediated stereotyped behavior (indicative of postsynaptic DA agonism) and blockade of 5-HTP-induced head twitches. Lisuride displaced specific ligand binding from putative S1a, S1b and S2 receptors at nanomolar concentrations, and other drugs that blocked 5-HTP-induced head twitches also displaced binding at S2 sites. It is proposed that lisuride may have agonist properties at S1a receptors mediating the 5-HT syndrome but antagonist properties at S2 receptors mediating 5-HTP-induced head twitching.

5-Hydroxytryptophan↗
PubMed1984

Dibenz[b,e]oxepinalkanoic acids as nonsteroidal antiinflammatory agents. 4. Synthesis and evaluation of 4-(4,10-dihydro-10-oxothieno[3,2-c] [1]benzoxepin-8-yl)butanol and -butyric acid and related derivatives.

4,10-Dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-acetic acid (6) was previously reported as a potent antiinflammatory-analgesic agent characterized by an impressive therapeutic ratio in comparison with indomethacin. With the goal of finding compounds that might display even more favorable therapeutic ratios and/or enhanced antiinflammatory/analgesic properties in comparison to 6, we synthesized 4-(4,10-dihydro-10-oxothieno [3,2-c][1]-benzoxepin-8-yl) butanol (4b) and -butyric acid (5a) and a series of related derivatives. All compounds were evaluated for potential analgesic activity in the phenylquinone-induced writhing (PQW) assay, for antiinflammatory activity in the carrageenan-induced paw edema (CPE) model and, where warranted, for gastric irritation (GI) liability. Of the compounds investigated, 4b (HP 573) displays moderate analgesic-like activity in PQW, is approximately half as potent as indomethacin or 6 as an antiinflammatory agent in the CPE, and is characterized by an extremely low propensity to induce GI as reflected by comparison of the therapeutic ratios (GI ED50/CPE ED50: 4b greater than 46, 6 = 9.9, indomethacin = 0.4). Compound 4b was selected for clinical evaluation.

Animals↗
PubMed1984

(+/-)-4-Aryl-4,5-dihydro-3H-1,3-benzodiazepines. 3. 2-Phenyl and 2-amino analogues as potential antihypertensive agents.

A series of 2-phenyl- and 2-amino-4-aryl-4,5-dihydro-3H-1,3-benzodiazepines was prepared and submitted for broad biological screening, including evaluation for potential antihypertensive activity. Compound 4a [(+/-)-4,5-dihydro-2,4-diphenyl-3-methyl-3H-1,3-benzodiazepine hydrochloride] was the most active member of the series in the spontaneously hypertensive rat (SHR) model, producing a 56 mmHg decrease in systolic blood pressure at an oral screening dose of 50 mg/kg. The synthesis of 4a analogues containing nuclear substituents in the 4-phenyl moiety resulted in a marked decrease of antihypertensive activity. It was not possible to improve on the antihypertensive properties of 4a through further synthetic modifications.

Animals↗
PubMed1982

Comparison of the pharmacological characteristics of 5 HT1 and 5 HT2 binding sites with those of serotonin autoreceptors which modulate serotonin release.

The abilities of various 5-hydroxytryptamine (5 HT) receptor agonists to inhibit the K+-evoked release of 3H-5 HT from prelabelled synaptosomal preparations of rat hypothalamus were studied. In addition, the abilities of various 5 HT receptor agonists and antagonists to compete with 3H-5 HT and 3H-spiperone binding to 5 HT1 and 5 HT2 sites, respectively, were determined. The orders of potency of the agonists for inhibiting K+-evoked 3H-5 HT release and for inhibiting 3H-5 HT and 3H-spiperone binding were then compared. Likewise, the abilities of the antagonists to block the inhibitory effect of 5 HT on its own K+-evoked release (data from previous studies) were compared to the affinities of these compounds for the 3H-5 HT and 3H-spiperone binding sites. A significant correlation was obtained between the effects of the agonists on K+-evoked 3H-5 HT release and 3H-5 HT binding but not 3H-spiperone binding. Furthermore, the antagonists which have been demonstrated to block the inhibitory effect of 5 HT on its own release (methiothepin, methysergide, metergoline and quipazine) had higher affinities for the 3H-5 HT binding site than the other antagonists. A similar correlation could not be made between antagonist activity at the 5 HT autoreceptor and affinity for the 3H-spiperone binding site. These results demonstrate that the 5 HT autoreceptor and the 5 HT1 binding site have similar pharmacological characteristics. On this basis, it is suggested that 5 HT autoreceptor and the 5 HT1 binding site may be related 5 HT receptor sites.

Animals↗
PubMed1982

The serotonin autoreceptor: antagonism by quipazine.

The purpose of this study was to attempt to reproduce previous findings regarding the antagonist specificity of the 5HT autoreceptor and to find additional antagonists of this receptor. Crude synaptosomal preparations of the rat hypothalamus were loaded with [3H]5HT, placed on glass microfiber filters and superfused with modified Krebs--Henseleit buffer at 37 degrees C. The release of [3H]5HT was stimulated by raising the buffer K+ concentration and was Ca2+-dependent. In the presence of 100 nM fluoxetine (a selective 5HT uptake inhibitor), exogenous 5HT inhibited the K+-induced release of [3H]5HT but did not affected basal [3H]5HT release. The K+-induced [3H]5HT release was maximally inhibited by 30 nM 5HT to a level of 66.4 +/- 4.0% of control. The concentration of 5HT required to inhibit half-maximally K+-induced [3H]5HT release was approx. 7 nM. Methiothepin and quipazine were found to block the inhibition of K+-induced [3H]5HT release by exogenous 5HT (30 nM). The IC50S for blockade of the effects of 5HT were approx. 3.8 and 670 nM for methiothepin and quipazine, respectively. Several other putative 5HT antagonists, the dopamine receptor antagonist, spiperone and the alpha receptor antagonist, phentolamine, were without effect. Thus, the 5HT autoreceptor appears to have a unique specificity for certain 5HT antagonists. In addition, blockade of 5HT autoreceptors may be one mechanism by which quipazine produces behavioral effects characteristic of a 5HT receptor agonist.

Animals↗
PubMed1982

Ketamine inhibits serotonin uptake in vivo.

Anesthetic (120 and 160 mg/kg. i.p.) and subanesthetic (80 mg/kg) doses of ketamine HCl were found to prevent completely the depletion of whole brain serotonin (5-HT) by p-chloramphetamine (PCA). Furthermore, ketamine HCl (160 mg/kg) completely blocked the depletion of 5-HT by PCA in every individual brain region studied (Midbrain-thalamus, hypothalamus, striatum, hippocampus and cortex). Administration of ketamine alone had no effect on brain 5-HT levels. Nialamide (a monoamine oxidase (MAO) inhibitor) and fluoxetine (a selective 5-HT uptake inhibitor) also prevented the depletion of 5-HT by PCA. However, of these three agents, only nialamide prevented the depletion of 5-HT by reserpine. These results suggest that ketamine blocks PCA-induced 5-HT depletion by inhibiting 5-HT uptake and not by inhibiting MAO. Ketamine only weakly affected either [3H]5-HT or [3H]spiroperidol binding to 5-HT1 and 5-HT2 receptors respectively even at concentrations as high as 1 mM. These data support the contention that the primary direct effect of ketamine on serotonergic systems is the blockade of 5-HT uptake and that blockade of 5-HT uptake may mediate some of the behavioral effects of ketamine, such as analgesia.

Animals↗
PubMed1982

Ketamine inhibits serotonin synthesis and metabolism in vivo.

Ketamine (160 mg/kg, i.p.) was found to reduce the accumulation of 5-hydroxytryptophan (5-HTP) in whole brain following inhibition of L-aromatic amino acid decarboxylase with 50 mg/kg of 3-hydroxybenzylhydrazine (NSD-1015). Smaller doses of ketamine did not affect whole brain 5-HTP accumulation. However in regional studies, 80 mg/kg of ketamine significantly reduced 5-HTP accumulation in the spinal cord and the midbrain-thalamus. A dose of 160 mg/kg ketamine also reduced 5-HTP accumulation in the spinal cord and midbrain-thalamus and in the medulla-pons, striatum and cortex as well. No significant changes in 5-HTP accumulation were observed in the hypothalamus or hippocampus. Ketamine (160 mg/kg) also reduced whole brain 5-hydroxyindoleacetic acid (5-HIAA) levels and slightly elevated whole brain 5-hydroxytryptamine (5-HT) levels. Smaller doses did not affect either 5-HIAA or 5-HT levels. Ketamine did not affect whole brain tryptophan levels nor did it inhibit [3H]tryptophan uptake or conversion to [3H]5-HT in vitro. These data demonstrate that ketamine reduced both 5-HT synthesis and metabolism in vivo. Since ketamine did not affect brain tryptophan levels nor did it inhibit 5-HT in vitro, the reduction of 5-HT turnover following ketamine administration appears to be a neuronal, adaptive phenomenon possibly occurring in response to a blockade of 5-HT uptake by ketamine.

Animals↗
PubMed1982

(+/-)-4-Aryl-4,5-dihydro-3H-1,3-benzodiazepines. 1. Synthesis and evaluation of (+/-)-4,5-dihydro-2,3-dimethyl-4-phenyl-3H-1,3-benzodiazepine and analogues as potential antidepressant agents.

A series of (+/-)-4,5-dihydro-4-phenyl-3H-1,3-benzodiazepines and (+/-)-4,5-dihydro-4-phenyl-1H-1,3-benzodiazepines was synthesized as part of a program to develop novel psychotropics. Of these compounds, (+/-)-4,5-dihydro-2,3-dimethyl-4-phenyl-3H-1,3-benzodiazepine (10a, HRP 543) emerged as a potential antidepressant. In in vivo mouse tests (inhibition of tetrabenazine-induced ptosis and potentiation of yohimbine toxicity) which are predictive of antidepressant-like activity, 10a is comparable to amitriptyline. The similarity is also maintained in vitro, as both 10a and amitriptyline inhibit norepinephrine and serotonin uptake into rat brain synaptosomes. No significant inhibition of rat brain monoamine oxidase A or B was found with 10a, nor did the compound potentiate tryptamine-induced seizures. On chronic administration, the number of cortical beta-adrenergic receptor sites was similarly reduced by 10a and desipramine. The anticholinergic activity of clinically useful antidepressants, such as amitriptyline, is a proposed cause of side effects which reduce patient compliance. In contrast to the tricyclics, 10a apparently lacks anticholinergic activity, as evidenced in vitro by negligible displacement of [3H]quinuclidinyl benzylate from rat brain muscarinic receptors and in vivo by insignificant antagonism of the cholinergic stimulation produced by physostigmine or oxotremorine. These data suggest that 10a may be clinically useful as a novel nontricyclic antidepressant which is devoid of anticholinergic side-effect liability. Further evaluation of 10a in nonrodent species is in progress.

Aggression↗
PubMed1982

(+/-)-4-Aryl-4,5-dihydro-3H-1,3-benzodiazepines. 2. Nuclear-substituted analogues of (+/-)-4,5-dihydro-2,3-dimethyl-4-phenyl-3H-1,3-benzodiazepine and (+/-)-4,5-dihydro-2-ethyl-3-methyl-4-phenyl-3H-1,3-benzodiazepine as potential antidepressant agents.

Antidepressant-like activity, as evidenced by marked inhibition of tetrabenazine-induced ptosis, was previously reported for (+/-)-4,5-dihydro-4-phenyl-3H-1,3-benzodiazepine derivatives. Since optimal antitetrabenazine activity was associated with (+/-)-4,5-dihydro-2,3-dimethyl-4-phenyl-3H-1,3-benzodiazepine (9k, HRP 543) and the 2-ethyl-3-methyl analogue (10k), the synthesis and evaluation of nuclear-substituted derivatives of these two compounds was also investigated. The initial synthesis involved Friedel-Crafts acylation of substituted benzenes with 2-nitrophenylacetyl chloride to afford 1-aryl-2-(2-nitrophenyl)ethanones 2, which were converted in five steps to (+/-)-alpha-aryl-N-methyl-2-nitrobenzeneethanamines 7. Greater flexibility with respect to the introduction of nuclear substituents was achieved by conversion of 2-nitrotoluene derivatives to 2 via acylation of intermediate beta-(dimethylamino)-2-nitrostyrenes with various aroyl chlorides and hydrolysis. Reductive amination of 2 with methylamine and sodium cyanoborohydride afforded 7 directly and significantly reduced the number of synthetic steps. Reduction of 7a-j to diamines 8a-j and cyclization with appropriate ortho esters gave nuclear-substituted analogues of 9k and 10k. Marked antitetrabenazine activity was associated with many of these compounds. Significant enhancement of activity with respect to the unsubstituted analogues 9k and 10k was not observed, with the exception of 9c which appeared to be slightly more potent than 9k.

Amphetamine↗
PubMed1981

Synthesis of spiro[isobenzofuran-1(3H),4'-piperidines] as potential central nervous system agents. 6. Synthesis, 13C NMR, and biological evaluation of cis- and trans-4-amino-3'-arylspiro[cyclohexane-1,1'(3'H)-isobenzofuran] derivatives.

4-(Dimethylamino)- and 4-(methylamino)-3'-arylspiro[cyclohexane-1,1'(3'H)-isobenzofuran] derivatives were prepared as analogues of previously reported 3-arylspiro[isobenzofuran-1(3H),4'-piperidines]. Metalation of benzanilide with n-butyllithium, addition of 4-(dimethylamino)cyclohexanone, and acidification afforded a mixture of cis- and trans-4-(dimethylamino)spiro[cyclohexane-1,1'(3'H)-isobenzofuran]-3'-ones (1a,b), which were separated by fractional crystallization. Addition of aryllithium or aryl Grignard reagents to 1a,b and formic acid reduction afforded cis- and trans-4-(dimethylamino)-3'-arylspiro[cyclohexane-1,1'(3'H)-isobenzofurans] 3a-f, which were converted to secondary amine analogues 5a-e. Tentative stereochemical assignments are based on chemical arguments and are supported by 13C NMR chemical shift data. Marked inhibition of tetrabenazine-induced ptosis is a property of most antidepressants, and significant antitetrabenazine activity is observed for several of these compounds. Optimal antitetrabenazine activity is associated with the cis-3'-phenyl series, and the cis secondary amine 5a is approximately twice as potent as the cis tertiary amine 3a. The various compounds are relatively weak with respect to potentiation of L-5-hydroxytryptophan-induced seizures.

Animals↗
PubMed1981

The biosynthesis of the antibiotic pyrrolnitrin by Pseudomonas aureofaciens.

Feeding experiments with tryptophan samples labeled specifically with radioactive and stable isotopes have shown that Pseudomonas aureofaciens converts this amino acid into pyrrolnitrin in such a way that the indole nitrogen gives rise to the nitro group, the amino group becomes the pyrrole nitrogen, C-3 of the precursor side chain becomes C-3 of the antibiotic, and H-2 of the indole ring and H-alpha of the side chain give rise to H-5 and H-2 of pyrrolnitrin, respectively. Only the L-isomer of tryptophan is incorporated with retention of the alpha-hydrogen and the amino nitrogen. From the D-isomer the labels from these two positions are lost. The obvious conclusion that L-tryptophan is the more immediate precursor is, however, contradicted by the better incorporation of D- than L-tryptophan into the antibiotic. Several potential pathway intermediates were evaluated for incorporation and 4-(0-aminophenyl)-pyrrole was found to be a good precursor. The results area discussed in terms of a plausible pathway for pyrrolnitrin biosynthesis.

Antifungal Agents↗