Ligand-directed multifunctional signaling of histamine H1 receptors.
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Adenylyl Cyclases↗
Biomedical subjects
R G Booth
Publications and source records attributed to R G Booth.
Functional heterogeneity of histamine H(1) receptors.
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Animals↗
A novel phenylaminotetralin (PAT) recognizes histamine H1 receptors and stimulates dopamine synthesis in vivo in rat brain.
A series of novel phenylaminotetralins (PATs) previously was shown to recognize discrete binding sites that are stereoselectively labeled by [3H]-(-)-trans-1-phenyl-3-N,N-dimethylamino-1,2,3,4-tetrahydronaphthalen e (H2-PAT) and highly localized in catecholaminergic nerve terminal regions in guinea pig forebrain. Furthermore, certain PATs stimulate tyrosine hydroxylase and dopamine synthesis in guinea pig and rat brain in vitro. In the current studies, we characterized sites labeled by [3H]-(-)-trans-H2-PAT and measured effects of PATs on dopamine synthesis in vivo in rat brain. [3H]-(-)-Trans-H2-PAT binds saturably (Bmax approximately 13 fmol/mg protein) and with high affinity (K(D) approximately 0.5 nM) to a single population of sites in rat brain. The ligand binding profile of [3H]-(-)-trans-H2-PAT labeled sites is very similar to histamine H1 receptors labeled with [3H]-mepyramine. After i.c.v. injection to rats, (+/-)-trans H2-PAT (4-40 nmoles/kg) stimulates dopamine synthesis (to about 180% of control levels) selectively in the limbic brain region nucleus accumbens vs. the extrapyramidal region striatum; this effect is fully blocked by (+/-)-cis-H2-PAT and the H1 antagonist triprolidine. At higher doses (> 40 nmoles/kg), the observed stimulation of dopamine synthesis is attenuated to control levels, likely due to activation of feedback mechanisms resulting from non-receptor mediated displacement of intraneuronal dopamine. We propose that PATs represent a novel class of ligands for H1 receptors that can modulate tyrosine hydroxylase activity and dopamine synthesis in the limbic region of mammalian forebrain.
Animals↗
Synthesis, evaluation, and comparative molecular field analysis of 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes as ligands for histamine H(1) receptors.
A series of 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes (1-phenyl-3-aminotetralins, PATs) previously was found to modulate tyrosine hydroxylase activity and dopamine synthesis in rodent forebrain through interaction with a binding site labeled by [(3)H]-(-)-(1R,3S)-trans-H(2)-PAT. Recently, we have discovered that PATs also bind with high affinity to the [(3)H]mepyramine-labeled H(1) receptor in rat and guinea pig brain. Here, we report the synthesis and biological evaluation of additional PAT analogues in order to identify differences in binding at these two sites. Further molecular modifications involve the pendant phenyl ring as well as quaternary amine compounds. Comparison of about 38 PAT analogues, 10 structurally diverse H(1) ligands, and several other CNS-active compounds revealed no significant differences in affinity at [(3)H]-(-)-trans-H(2)-PAT sites versus [(3)H]mepyramine-labeled H(1) receptors. These results, together with previous autoradiographic brain receptor-mapping studies that indicate similar distribution of [(3)H]-(-)-trans-H(2)-PAT sites and [(3)H]mepyramine-labeled H(1) receptors, suggest that both radioligands label the same histamine H(1) receptors in rodent brain. We also report a revision of our previous comparative molecular field analysis (CoMFA) study of the PAT ligands that yields a highly predictive model for 66 compounds with a cross-validated R(2) (q(2)) value of 0.67. This model will be useful for the prediction of high-affinity ligands at radiolabeled H(1) receptors in mammalian brain.
Animals↗
Putative sigma(3) sites in mammalian brain have histamine H(1) receptor properties: evidence from ligand binding and distribution studies with the novel H(1) radioligand [(3)H]-(-)-trans-1-phenyl-3-aminotetralin.
A novel phenylaminotetralin (PAT) radioligand, [(3)H]-(1R, 3S)-(-)-trans-1-phenyl-3-dimethylamino-1,2,3,4-tetrahydronaphthalene ([(3)H]-[-]-trans-H(2)-PAT), is shown here to label a saturable (B(max)=39+/-6 fmol/mg protein) population of sites with high affinity (K(d)=0.13+/-0.03 nM) in guinea pig brain. Consistent with previous studies which showed that PATs stimulate catecholamine (dopamine) synthesis in rat striatum, autoradiographic brain receptor mapping studies here indicate that [(3)H]-(-)-trans-H(2)-PAT-labeled sites are highly localized in catecholaminergic nerve terminal fields in hippocampus, nucleus accumbens, and striatum in guinea pig brain. Competition binding studies with a broad range of CNS receptor-active ligands and CNS radioreceptor screening assays indicate that the pharmacological binding profile of brain [(3)H]-(-)-trans-H(2)-PAT sites closely resembles histamine H(1)-type receptors. Comparative studies using the histamine H(1) antagonist radioligand, [(3)H]mepyramine, indicate that the H(1) ligand binding profile and guinea pig brain distribution of H(1) receptors and [(3)H]-(-)-trans-H(2)-PAT sites are nearly identical; moreover, both sites have about 40-fold stereoselective affinity for (-)- over (+)-trans-H(2)-PAT. These results are discussed in light of previous studies which suggested that PATs stimulate dopamine synthesis through interaction with a novel sigma-type (sigma(3)) receptor in rodent brain; it now appears instead that PATs represent a new class of ligands for brain histamine H(1) receptors that can be stereoselectively labeled with [(3)H]-(-)-trans-H(2)-PAT.
Animals↗
2-Phenylaminoadenosine stimulates dopamine synthesis in rat forebrain in vitro and in vivo via adenosine A2 receptors.
The adenosine agonist 2-phenylaminoadenosine (PAD) stimulated tyrosine hydroxylase activity in rat striatum in vitro. This effect was selectively blocked by the A2 antagonist 8-chlorostyrylcaffeine (CSC), suggesting an A2 receptor-mediated mechanism. PAD also produced a corresponding increase in striatal adenylyl cyclase activity. Using an in vivo model that measures presynaptic effects of drugs at dopamine nerve terminals, intracerebroventricular administration of PAD to rats stimulated tyrosine hydroxylase activity in striatum in a manner that was selectively blocked by CSC. These results suggest that PAD stimulates adenylyl cyclase and tyrosine hydroxylase activity, with a corresponding increase in dopamine synthesis, by activation of presynaptic A2-type receptors in mammalian forebrain.
Adenosine↗
Effects of polychlorinated biphenyls (PCBs) on brain tyrosine hydroxylase activity and dopamine synthesis in rats.
Literature reports suggest that polychlorinated biphenyls (PCBs) may alter dopaminergic neurotransmission in mammalian forebrain. In vitro, PCBs can decrease dopamine levels in PC 12 cells and studies of the structure-activity relationship (SAR) indicate that ortho-substituted (non-coplanar) PCB congeners are more active than para-substituted (coplanar) congeners. This report tested the hypothesis that ortho-substituted PCBs can selectively (vs para-substituted congeners) decrease dopamine synthesis in mammalian forebrain by inhibiting the activity of tyrosine hydroxylase, the rate-limiting enzyme in dopamine biosynthesis. In vitro effects of individual PCB congeners on activity of striatal tyrosine hydroxylase from two different rat strains were assessed. It was found that certain ortho-substituted PCB congeners (e.g., 2,2'-DCB) can inhibit tyrosine hydroxylase activity and dopamine synthesis by nearly 40% in minces of corpus striatum prepared from Sprague-Dawley and Long-Evans hooded rats. Comparatively, the ortho, meta-substituted PCB congener 2,2',5,5'-TeCB inhibited tyrosine hydroxylase activity only in striatal minces obtained from Sprague-Dawley rats, suggesting that genetic factors may influence the susceptibility of mammals to effects of PCBs that compromise brain dopamine synthesis. The PCB-induced inhibition of tyrosine hydroxylase activity in mammalian forebrain observed here appears to occur through indirect and as yet unknown mechanisms.
Animals↗
1-Phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes and related derivatives as ligands for the neuromodulatory sigma 3 receptor: further structure-activity relationships.
A series of 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes (1-phenyl-3-aminotetralins, PATs) previously was found to stimulate tyrosine hydroxylase activity and dopamine synthesis in rat brain through interaction with a novel sigma 3 receptor. Specifically, the trans-1R,3S-(-) isomer of H2-PAT showed highest affinity for sigma 3 receptors and also produced maximal stimulation of tyrosine hydroxylase activity and dopamine synthesis, as compared to the trans-1S,3R-(+) isomer. Affinity for sigma 3 receptors and functional potency at stimulating dopamine synthesis were attenuated either by altering the position or dimethyl substitution pattern of the amino group or by hydroxylating the tetralin aromatic ring. A preliminary binding model can accommodate many PAT analogs and several non-PATs with a wide range of affinities for the sigma 3 receptor. Here, we report the synthesis and evaluation of additional analogs in order to expand previous structure-activity relationship studies. Further molecular modifications include synthesis of 1-phenyl-1-methyl-3-amino, 1-phenyl-2-amino, 1-phenyl-3-(trimethylammoniumyl), and 1-phenyl-3-(phenylalkyl) analogs, as well as ring-expanded tetrahydrobenzocycloheptenes. In general, the above modifications decreased sigma 3 receptor affinity and, in some cases, caused a reversal of the sigma 3 binding selectivity of trans- versus cis-PATs found previously. Most analogs were selective for sigma 3 receptors and showed little or no affinity for either sigma 1/sigma 2 or dopamine D1, D2, and D3 receptors. N-Phenylalkyl substituents, such as N-phenylethyl, however, endowed the 1-phenyl-3-aminotetralins with enhanced sigma 1/sigma 2 and dopamine receptor affinity while decreasing sigma 3 affinity, thus abolishing sigma 3 selectivity.
Animals↗
Conformational analysis, pharmacophore identification, and comparative molecular field analysis of ligands for the neuromodulatory sigma 3 receptor.
Molecular modeling studies were carried out on a series of 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes (phenylaminotetralins, PATs), several PAT structural analogs, and various non-PAT ligands that demonstrate a range of affinities for a novel sigma 3 receptor linked to stimulation of tyrosine hydroxylase and dopamine synthesis in rodent brain. In an effort to develop a ligand-binding model for the sigma 3 receptor, a pharmacophore mapping program (DISCO) was used to identify structural features that are common to ligands that exhibit moderate to high binding affinity for sigma 3 sites. DISCO then was utilized to propose a common pharmacophoric region that included one low-energy conformation of each compound in the training set. The resulting alignment was utilized in a comparative molecular field analysis (CoMFA) study in an attempt to correlate the steric and electrostatic fields of the molecules with the respective binding affinities at the sigma 3 receptor. A suitably predictive model was obtained from the CoMFA analysis which will be employed in the development of additional PAT analogs that could potentially display high affinity and selectivity for the sigma 3 receptor. The excluded volumes which resulted from comparing molecular volumes of active and inactive compounds were visualized to examine the limits of steric tolerance imposed by the sigma 3 receptor.
Animals↗
Actions of (+/-)-7-hydroxy-N,N-dipropylaminotetralin (7-OH-DPAT) on dopamine synthesis in limbic and extrapyramidal regions of rat brain.
The proposed D3-selective ligand (+/-)-7-hydroxy-N,N-dipropylaminotetralin (7-OH-DPAT) inhibited tyrosine hydroxylase in vitro (IC50 = 0.6-0.7 microM) and dihydroxyphenylalanine (DOPA) accumulation in vivo (ID50 = 4.8-6.4 mg/kg) in two autoreceptor models in extrapyramidal and limbic tissue in rat forebrain, without consistent regional selectivity. Some limbic selectivity (ID50 = 10 vs. 29 mg/kg) was found in an in vivo model permitting expression of postsynaptic D3 and D2 receptor activity. The effects were partially blocked by S(-)-eticlopride alone, and fully after reserpine pretreatment. The results suggest that 7-OH-DPAT activates D3 or D2 autoreceptors, alters dopamine storage or release, and may interact with some limbic selectivity at postsynaptic D3 and D2 receptors as a partial agonist.
Animals↗
Gastric lymphoma.
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Helicobacter Infections↗
Synthesis and pharmacological evaluation of 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes as ligands for a novel receptor with sigma-like neuromodulatory activity.
Certain novel 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes (1-phenyl-3-aminotetralins, PATs) produced stimulation (ca. 30% above basal levels) of tyrosine hydroxylase (TH) activity at 0.1 microM concentrations in rodent brain tissue. This effect on TH was blocked by the putative sigma-receptor antagonist BMY-14802, suggesting involvement of a novel neuromodulatory sigma-like receptor. Within the new phenylaminotetralin series, a correlation was found between the ability to stimulate TH and the potency to compete for binding sites labeled by (+/-)-[3H]1-phenyl-3-(N,N-dimethylamino)-6-chloro-7-hydroxy-1,2,3,4- tetrahydronaphthalene ([3H](+/-)-4). trans-Catechol analogs had low affinity for [3H]4 sites, and although they inhibited TH activity, this effect was not blocked by known sigma or dopamine antagonists. Analogs with dihydroxy substituents (catechols), as well as nitrogen substituents larger than methyl, had little affinity for [3H]4 binding sites and did not significantly affect TH activity. The pharmacology of the [3H]4 binding site is unique from that of any known sigma or dopamine receptor, thus the effects appear to be mediated by a previously uncharacterized binding site/receptor. The site has stereoselectivity for the (1R,3S)-(-)-isomer of 1-phenyl-3-(N,N-dimethylamino)-1,2,3,4-tetrahydronaphthalene; this isomer is also more active at stimulating TH. Thus, certain 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes appear to be selective probes of a novel receptor type that mediates sigma-like neuromodulatory activity and may have pharmacotherapeutic utility in conditions in which modulation of dopamine function is important.
Animals↗
New sigma-like receptor recognized by novel phenylaminotetralins: ligand binding and functional studies.
Several novel phenylaminotetralins (PATs) cause functional changes in brain that are associated with binding to saturable, high affinity sites that are not identical to any known central nervous system receptor. These PATs were tested for their ability to cause receptor-mediated functional effects on tyrosine hydroxylase activity in corpus striatum from rat and guinea pig brain. (+/-)-(trans)-1-Phenyl-3-dimethylamino-6-chloro-7-hydroxy-1,2,3,4- tetrahydronaphthalene (CI, OH-PAT) increased tyrosine hydroxylase activity (by approximately 30-40%) at 0.1 microM. Higher concentrations inhibited enzyme activity by indirect mechanisms that may include displacement of intraneuronal dopamine. The 6,7-unsubstituted congener (+/-)-(trans)-1-phenyl-3-dimethylamino-1,2,3,4- tetrahydronaphthalene stimulated tyrosine hydroxylase by as much as 50-60% over basal activity, without displacement of dopamine. Similarly to certain (+)-benzomorphan sigma receptor ligands, the effects of both PATs to activate tyrosine hydroxylase were blocked competitively by the putative sigma antagonist BMY-14802. Radiolabeled [3H]CI,OH-PAT bound saturably and with high affinity to guinea pig brain membranes (Kd = 31 pm, Bmax = 6.5 fmol/mg of protein). The pharmacological profile of these binding sites was inconsistent with those of known sigma 1, sigma 2, dopaminergic, serotonergic, adrenergic, opioid, N-methyl-D-aspartate, or several other characterized central nervous system recognition sites. Together, these data suggest that these PATs may be agonists at a novel sigma-like site that has neuromodulatory activity that results in increases of brain catecholamine synthesis via activation of tyrosine hydroxylase.
Animals↗
Dopamine D1 autoreceptor function: possible expression in developing rat prefrontal cortex and striatum.
Synthesis-modulating dopamine (DA) autoreceptor function was studied in vivo using gamma-butyrolactone (GBL) to block propagation along DA axons. DA synthesis was measured by the accumulation of L-3,4-dihydroxyphenylalanine (L-DOPA) after inhibition of aromatic L-amino acid decarboxylase. GBL treatment markedly increased DOPA accumulation in both the striatum and prefrontal cortex of developing rats. The selective DA partial D1 agonist SKF-38393 inhibited this GBL-induced rise in DA synthesis in both the striatum and prefrontal cortex of 15- and 22-day-old rats, but not in adults. The effects of SKF-38393 in developing rats were mimicked by the non-catechol D1 partial agonist CY-208-243, and were blocked by the D1 antagonist SCH-23390, suggesting receptor mediation. The mixed D2/D3 agonist quinpirole attenuated DA synthesis in striatum of both two-week-old and adult rats, but failed to inhibit the GBL-induced increase in DA synthesis in the developing prefrontal cortex. These findings suggest that synthesis-modulating D1-like receptor function may emerge transiently in the developing mammalian forebrain. In the adult striatum these functions appear to be subsumed by D2-like receptors, whereas all synthesis-modulating DA receptor function in prefrontal cortex appears to be essentially lost with maturation.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
(+)-6,7-benzomorphan sigma ligands stimulate dopamine synthesis in rat corpus striatum tissue.
The benzomorphan sigma ligands, (+)-N-allylnormetazocine (NANM) and (+)-pentazocine, but not (+)-cyclazocine, stereospecifically stimulated dopamine synthesis in minces of rat corpus striatum by 15-23% over basal values at 0.1-1.0 microM. The effect of (+)-NANM and (+)-pentazocine was blocked by the reported sigma antagonist, BMY-14802 but not by the opiate antagonist naloxone. These results suggest that these (+)-benzomorphans may act as agonists at putative sigma heteroreceptors on striatal nerve terminals, or through an indirect mechanism, to modulate dopamine synthesis.
Animals↗
Inhibition of dopamine synthesis in rat striatal minces: evidence of dopamine autoreceptor supersensitivity to S(+)- but not R(-)-N-n-propylnorapomorphine after pretreatment with fluphenazine.
This study provides in vitro evidence that rats pretreated with fluphenazine for 10 days, but not acutely, developed moderate but significant striatal autoreceptor supersensitivity as measured by the ability of S(+)-NPA, a selective DA autoreceptor agonist and very weak postsynaptic agonist, to inhibit tyrosine hydroxylase activity. In contrast, autoreceptor supersensitivity was not found with the nonselective auto- and postsynaptic receptor agonist R(-)-NPA. Presumably, this effect represents some modification of a presynaptic regulatory mechanism controlling DA synthesis which can occur despite a reportedly high striatal DA autoreceptor reserve in rat striatum [2, 7]. Such a mechanism, by tending to reduce synaptic availability of DA, may contribute to tolerance to the transient, early DA-synthesis stimulating actions of acutely administered neuroleptics [4], and help to counterbalance increases in postsynaptic DA receptor abundance and sensitivity associated with long-term neuroleptic treatment.
Animals↗
Adenosine A2 stimulation of tyrosine hydroxylase in rat striatal minces is reversed by dopamine D2 autoreceptor activation.
The adenosine agonist, 2-chloroadenosine, stimulated tyrosine hydroxylase activity in rat striatal minces; this effect was attenuated by activation of dopamine (DA) D2 autoreceptors with N-n-propylnorapomorphine and antagonized by theophylline. Forskolin and 8-bromo-cAMP also increased tyrosine hydroxylase activity and their effects were not altered by 2-chloroadenosine. D1, alpha, beta and 5-HT agonists did not affect tyrosine hydroxylase activity. Evidently, A2 receptors on DA nerve terminals stimulate striatal DA synthesis and this effect is negatively modulated by D2 autoreceptors, probably via changes in intracellular cAMP levels.
2-Chloroadenosine↗
In vivo intracerebral microdialysis studies in rats of MPP+ analogues and related charged species.
The in vivo dopaminergic neurotoxic properties of 45 MPTP and MPP+ analogues and related compounds were examined by an intrastriatal microdialysis assay in conscious rats. MPP(+)-like toxicity, as evidenced by the irreversible effects on DA release and enhancement of lactate formation, was observed with a variety of structural types although no compound was more toxic than MPP+. The following global structure-toxicity relationships could be derived: (1) only permanently charged compounds showed neurotoxic effects; (2) with the exception of amino groups, hydrophilic substituents abolished toxicity; (3) activity was enhanced by lipophilic groups although increased steric bulk around the nitrogen atom tended to decrease activity; (4) nonaromatic, quaternary systems (methiodide of MPTP, guanidinium derivatives) were only weakly toxic; and (5) certain bi- and tricyclic systems, including putative metabolites of potential endogenous MPTP-like compounds, were weakly toxic. The lack of toxic effects following perfusions with DA itself confirmed that MPTP dopaminergic neurotoxicity is not likely to be mediated by the MPP(+)-induced release of DA. With some interesting exceptions, these in vivo data correlate reasonably well with in vitro data on the nerve terminal uptake properties and the inhibitory effects on mitochondrial respiration of these compounds.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗