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W Hoss

Publications and source records attributed to W Hoss.

At least 19 recordsLinked to original sources
PubMed1992

Steric and electronic requirements for muscarinic receptor-stimulated phosphoinositide turnover in the CNS in a series of arecoline bioisosteres.

A series of arecoline derivatives was utilized to assess steric and electronic effects important for activating muscarinic receptors in the CNS. Arecoline derivatives in which the methyl ester moiety was replaced by hexyloxy-1,2,5-oxadiazole (2b), hexyloxythiophene (3b) or hexyloxypyrazine (4b) were compared with the hexyloxy-1,2,5-thiadiazole compound (1b) (Hexyloxy-TZTP), known from previous work to be active as an M1/M3 partial agonist. MNDO calculations showed that the N-S bonds of the alkoxythiadiazole ring were highly polarized with the ability to form H-bonds to the N's. On the other hand, the smaller oxadiazole had lower polarities in the N-O bonds and reduced ability to form H-bonds, the thiophene was of comparable size to the thiadiazole and had large C-S bond polarities without the H-bond capability and the pyrazine had limited ability to form H-bonds. The compounds were compared with respect to their abilities to stimulate phosphoinositide (Pl) turnover in the hippocampus of the rat brain. 1b was more active than 2b-4b for stimulating the Pl turnover response. The data suggest that the ability to form H-bonds is an important factor for the ability of 1 to stimulate M1 muscarinic receptors in the CNS.

Animals↗
PubMed1992

Stereoselective binding and activity of oxotremorine analogs at muscarinic receptors in rat brain.

The activities of the enantiomers of BM-5 were examined to measure muscarinic cholinergic selectivity in the central nervous system. Autoradiographic studies assessed the ability of each enantiomer to inhibit the binding of [3H]-(R)-quinuclidinyl benzilate ([3H]-(R)-QNB) to muscarinic receptors in the rat brain. (+)-(R)-BM-5 inhibited [3H]-(R)-QNB binding to rat brain sections at concentrations below 1.0 microM, while 100-fold higher concentrations of (-)-(S)-BM-5 were required for comparable levels of inhibition. Analysis of the autoradiograms indicated that both stereoisomers had a similar distribution of high affinity binding sites. Each enantiomer displayed higher affinity for muscarinic receptors in the superior colliculi and lower affinity for receptors in the cerebral cortex and hippocampus. (+)-(R)-BM-5 and oxotremorine inhibited adenylyl cyclase activity in the cerebral cortex with efficacies comparable to that for acetylcholine. (+)-(R)-BM-5 was 26-fold more potent than (-)-(S)-BM-5 in inhibiting adenylyl cyclase. Oxotremorine-M and carbamylcholine stimulated phosphoinositide turnover in the cerebral cortex. Oxotremorine had lower activity and (+)-(R)-BM-5 was essentially inactive at comparable concentrations. The difference in activity of the two enantiomers indicates a remarkable stereochemical selectivity for muscarinic receptors. The stereoselectivity index is comparable for both the autoradiographic assays (48) and measures of adenylyl cyclase activity (26) in the cerebral cortex.

Adenylyl Cyclases↗
PubMed1991

Inhibition of carbachol-stimulated phosphoinositide turnover by U-50,488H in rat hippocampus--involvement of GTP-binding protein.

The effect of U-50,488H, a selective kappa-opioid agonist, on carbachol-stimulated phosphoinositide (PI) turnover response in rat hippocampal slices was examined. U-50,488H which stimulates PI turnover response in this preparation (Periyasamy and Hoss, 1990, Life Sci. 47, 219), inhibited carbachol-stimulated PI turnover in a concentration-dependent manner with an IC50 value of 33 +/- 9.0 microM. The inhibitory effect of U-50,488H was not blocked by the kappa-selective antagonists, e.g., nor-binaltorphimine (10 microM), and MR2266 (10 microM), or tetrodotoxin (1 microM) suggesting that the effect of U-50,488H was mediated neither through the kappa-receptors nor through the release of an endogenous neurotransmitter(s). A Lineweaver-Burke plot of the stimulation of PI turnover by carbachol in the presence and absence of U-50,488H showed that the Km was not changed (11.4 +/- 3.4 and 11.5 +/- 2.6 microM) whereas the Vmax was reduced from 3849 +/- 460 to 1534 +/- 31 cpm indicating that the inhibition was non-competitive. U-50,488H also inhibited guanosine 5'-[beta, gamma-imido]triphosphate (Gpp[NH]p)-stimulated PI turnover in rat hippocampal membranes in a concentration-dependent manner with an IC50 value of 33 +/- 12 microM.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1990

Biochemical and behavioral responses of pilocarpine at muscarinic receptor subtypes in the CNS. Comparison with receptor binding and low-energy conformations.

Pilocarpine was tested biochemically in vitro for its ability to stimulate phosphoinositide (PI) turnover in the hippocampus (M1/M3 responses) where it displayed 35% of the maximal carbachol response with an EC50 value of 18 microM, and low-Km GTPase in the cortex (M2 response), where it had 50% of the maximal carbachol response with an EC50 value of 4.5 microM. Behaviorally, pilocarpine was able to restore deficits in a representational memory task (sensitive to M1 antagonists) produced by intrahippocampal injections of AF64A. Twenty-three low-energy conformations of protonated pilocarpine were generated using the program MacroModel. The data indicate that pilocarpine is a partial agonist at both M1 and M2 muscarinic receptors in the CNS. Behaviorally, with respect to the memory task, M1 effects of pilocarpine apparently predominate. It also is conceivable that different conformations of pilocarpine are active as agonists at different muscarinic receptor subtypes.

Animals↗
PubMed1990

Biochemical and behavioral evidence for muscarinic autoreceptors in the CNS.

Muscarinic autoreceptors of the M2 subclass were examined in rat forebrain using a number of different methodologies, including receptor autoradiography and image analysis, regulation of acetylcholine release, phosphoinositide turnover, low-Km GTP hydrolysis, and behavioral analysis. The relatively minor population of M2 receptors in coronal sections was visualized by autoradiography and image analysis using [3H]quinuclidinyl benzilate in the presence of a concentration of pirenzepine that blocked most of M1 (and M4) receptors. The highest densities of M2 receptors in forebrain regions were found in the outer layers of the cortex, CA1 region of the hippocampus and striatum. The M2-, but not M1-selective antagonists were able to block the oxotremorine-induced attenuation of acetylcholine release in forebrain synaptosomes. Low concentrations of the M2-selective antagonist gallamine increased phosphoinositide turnover, which is thought to be an M1 postsynaptic response in the forebrain, in brain slices by a Ca2(+)-dependent mechanism. The M2-selective agonist oxotremorine produced a substantial stimulation of low-Km GTPase in cortical membranes, suggesting that M2 forebrain receptors are efficiently coupled to G-proteins in the cortex. Behavioral signs of cholinergic stimulation were observed after intracerebroventricular injections of M2-, but not M1-selective antagonists. It is suggested that a minor population of forebrain M2 receptors regulates acetylcholine release by a mechanism that includes coupling through G-proteins presynaptically at synapses for which the postsynaptic response involves phosphoinositide turnover. Selective blockade of these receptors produces both biochemical and behavioral signs of acetylcholine release.

Acetylcholine↗
PubMed1990

Differential coupling between muscarinic receptors and G-proteins in regions of the rat brain.

The coupling of muscarinic receptors to G-proteins in various regions of the rat brain was assessed by measuring carbachol-stimulated, low-Km GTPase. The inhibition of carbachol-stimulated GTPase by the M1-selective antagonist pirenzepine was compared to the affinity of pirenzepine for various nuclei within the regions as measured autoradiographically. The rank order of potency of carbachol for stimulating GTPase in various brain regions was similar to that for binding to receptors in those areas. The maximal specific activity (efficacy) of carbachol-stimulated GTPase varied independently of the distribution of total receptors or receptor subtypes. The overall potency of pirenzepine for inhibiting carbachol-stimulated GTPase was not correlated with the overall affinity of pirenzepine for muscarinic receptors in the regions. Comparing results in various brain regions, the data suggest that there are differences in the efficiency of coupling between muscarinic receptors and G-proteins. For example, the pons-medulla appeared to have a small population of pirenzepine-sensitive (M1 or M4) receptors that were coupled very efficiently to G-proteins, whereas in the hippocampus all muscarinic receptors, most of which are pirenzepine-sensitive, appeared to be weakly coupled to G-proteins. It is suggested that variable interactions between receptors and G-proteins may be an important factor in the overall coupling between receptor occupancy and cellular responses to acetylcholine as well as other hormones and transmitters.

Animals↗
PubMed1990

Subtype specificity of the muscarinic receptor-stimulated GTPase response in the rat cortex.

Subtype selective agonists and antagonists were used to examine the pharmacology of the low-Km GTPase response in the rat cortex. The M2-selective agonist oxotremorine, which is a weak partial agonist for M1 receptors in the brain, stimulated low Km GTPase activity with an EC50 value of 1.0 microM. Oxotremorine was nearly a full agonist and demonstrated no partial agonist activity in the presence of optimal concentrations of the agonists carbachol or oxotremorine-M, which stimulate all muscarinic responses. These data suggest that the GTPase response is associated with M2 receptors. Pirenzepine (M1-selective) and AF-DX 116 (M2-selective) inhibited oxotremorine-stimulated GTPase activities in cortex with IC50 values of 4.0 and 2.2 microM, respectively. Since pirenzepine is substantially more potent than AF-DX 116 for binding muscarinic receptors in the cortex (Messer et al., J. Med. Chem., 32 (1989) 1164), M2 receptors contribute more to the GTPase response than M1 receptors.

Animals↗
PubMed1990

Kappa opioid receptors stimulate phosphoinositide turnover in rat brain.

The effects of various subtype-selective opioid agonists and antagonists on the phosphoinositide (PI) turnover response were investigated in the rat brain. The kappa-agonists U-50,488H and ketocyclazocine produced a concentration-dependent increase in the accumulation of IP's in hippocampal slices. The other kappa-agonists Dynorphin-A (1-13) amide, and its protected analog D[Ala]2-dynorphin-A (1-13) amide also produced a significant increase in the formation of [3H]-IP's, whereas the mu-selective agonists [D-Ala2-N-Me-Phe4-Gly5-ol]-enkephalin and morphine and the delta-selective agonist [D-Pen2,5]-enkephalin were ineffective. The increase in IP's formation elicited by U-50,488H was partially antagonized by naloxone and more completely antagonized by the kappa-selective antagonists nor-binaltorphimine and MR 2266. The formation of IP's induced by U-50,488H varies with the regions of the brain used, being highest in hippocampus and amygdala, and lowest in striatum and pons-medulla. The results indicate that brain kappa- but neither mu- nor delta-receptors are coupled to the PI turnover response.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1990

Identification of four brain areas each enriched in a unique muscarinic receptor subtype.

The affinities of muscarinic agonists and antagonists were determined by autoradiography and image analysis in selected areas of the rat brain. IC50 values and Hill coefficients for the inhibition of the binding of 0.2 nM [3H]-QNB to dentate gyrus, superior colliculus, rhomboid thalamus and substantia nigra were measured in coronal sections. Pirenzepine displayed a high affinity for receptors in the dentate gyrus and AF-DX 116, the superior colliculus. Both pirenzepine and AF-DX 116 had high affinities for the substantia nigra and low affinities for the rhomboid thalamus. Gallamine displayed a 50-fold preference for superior colliculus over dentate gyrus receptors. Amitriptyline was less selective, showing a modest preference for substantia nigra receptors and 4-DAMP was essentially nonselective. Carbachol was the most selective agonist with a 4000-fold preference for superior colliculus over dentate gyrus receptors. Other agonists except RS 86 were also selective for superior colliculus receptors in the order carbachol much greater than arecoline greater than bethanechol greater than McN A343 = oxotremorine = pilocarpine.

Animals↗
PubMed1989

Autoradiographic analyses of agonist binding to muscarinic receptor subtypes.

The binding of four muscarinic receptor agonists to regions of rat brain was examined through quantitative autoradiographic techniques. Oxotremorine, arecoline, pilocarpine and bethanechol were chosen based on their different potencies and efficacies in muscarinic second messenger systems. Overall, the order of potency for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain slices was oxotremorine greater than pilocarpine = arecoline much greater than bethanechol. Regional assays of agonist potency indicated that all agonists were more selective for brainstem and thalamic regions than for hippocampal and cortical regions. The high selectivity of agonists for areas such as the paraventricular thalamus and the superior colliculus, which also display low affinity for pirenzepine, suggests that muscarinic agonists bind with higher affinity to M2 receptors. Of the four agonists examined, pilocarpine displayed the lowest selectivity for M2 receptors in that IC50 values for pilocarpine were only 3-fold higher in the hippocampal and striatal regions (e.g. CA3: 40.6 +/- 9.4 microM) than in thalamic and brainstem regions (e.g. paraventricular thalamus: 14.9 +/- 6.2 microM). Oxotremorine was 8-fold more potent in the brainstem and thalamus, while arecoline and bethanechol were, respectively, 19- and 100-fold more selective for brainstem and thalamic receptors. Scatchard analyses revealed heterogeneous binding profiles for some agonists within single brain regions, suggesting that multiple agonist sites exist even within regions of predominantly M1 or M2 receptors. For example, arecoline displayed curved Scatchard plots within the external layers of the cerebral cortex, layer CA1 of the hippocampus (predominantly M1 subtype), and the paraventricular thalamus (predominantly M2 subtype). The ability of agonists to recognize multiple sites within a single region may reflect the ability to recognize receptors coupled or uncoupled to second messenger systems through G-proteins.

Animals↗
PubMed1989

Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.

The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.

Animals↗
PubMed1988

Inhibition of phosphoinositide turnover by selective muscarinic antagonists in the rat striatum. Correlation with receptor occupancy.

In the rat corpus striatum, receptor occupancy and the inhibition of phosphoinositide turnover by muscarinic antagonists have been examined under very similar conditions with respect to tissue preparation and buffer composition. The results suggest a good correlation between receptor occupancy and inhibition by muscarinic antagonists, of the carbachol-stimulated turnover of inositol phospholipids, measured by the accumulation of [3H]inositol phosphates in the presence of 5 mM LiCl. In the presence of 10 mM carbachol (CCh), the accumulation of labeled inositol phosphates was increased 8-fold above basal levels (EC50 = 95 microM). Inclusion of antagonists resulted in a dose-dependent inhibition of the 0.1 mM CCh-stimulated inositol phosphate accumulation, with a rank order of potency of atropine greater than trihexyphenidyl greater than pirenzepine greater than or equal to gallamine. Radioligand binding studies with [3H]-l-quinuclidinyl benzilate [( 3H]QNB) in a cell aggregate preparation revealed a single class of saturable, high affinity [3H]QNB binding sites exhibiting a Kd of 74 pM and a Bmax of 2.85 pmol/mg protein. The antagonists examined were able to inhibit the binding of [3H]QNB with the same rank order of potency as for the inhibition of carbachol-stimulated phosphoinositide turnover (atropine greater than trihexyphenidyl greater than pirenzepine greater than or equal to gallamine). Although the inhibition of phosphoinositide turnover and [3H]QNB binding by the nonselective antagonist atropine was best described by interaction at a single site, inhibition of phosphoinositide turnover and [3H]QNB binding by both pirenzepine, which is selective for M1 receptors, and gallamine, which is selective for M2 receptors, is complex. Pirenzepine was much more potent than gallamine for both binding to receptors and inhibiting phosphoinositide turnover. Nonlinear curve-fitting analysis indicated that slope factors for inhibition of phosphoinositide turnover (analogous to Hill coefficient for binding) by only subtype selective antagonists were significantly less than unity. The above-mentioned antagonist interactions together with the apparently multicomponent stimulation of phosphoinositide turnover by carbachol suggest that phosphoinositide turnover may be coupled to more than one muscarinic receptor subtype in the corpus striatum.

Animals↗
PubMed1988

Characterization of low Km GTPase activity in rat brain: comparison of opioid and muscarinic receptor stimulation.

Guanosine 5'-triphosphate (GTP)-binding proteins (G-proteins) have an essential role in mediating the actions of drugs on neurotransmitter receptors by coupling them to their effectors with the attendant hydrolysis of GTP. The resulting GTPase activity was characterized in rat brain with a view toward selecting conditions under which specific hormone-stimulated activity could be monitored. Kinetic analysis with washed membranes suggested the presence of two distinct GTPases, a low Km GTPase with an apparent Km value of 0.35 +/- 0.04 microM and apparent Vmax of 108 pmol min-1 mg protein-1, together with a much higher Km component. Low Km (but not high Km) GTPase activity is stimulated by muscarinic and opioid agonists and inhibited by a nonhydrolyzable analogue of GTP, providing further evidence that the low Km component is a distinct enzyme. The activity of the low Km component is a linear function of protein concentration (20-100 micrograms/mL), time (2-10 min), and temperature (25-37 degrees C). The specific activity of the low Km component is selectively increased by approximately 50% in purified synaptic membranes compared with the washed membrane preparation. Both carbamylcholine-stimulated and basal low Km GTPase activities, but not the high Km component, are inhibited by a nonhydrolyzable analogue of GTP but not by the comparable analogue of ATP, demonstrating the specificity of low Km GTPase for guanine nucleotides. Opioid- and muscarinic-stimulated GTPase activities are additive in brain, suggesting that the two receptor systems are associated with different domains of G-proteins.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Selectivity of pirenzepine in the central nervous system. I. Direct autoradiographic comparison of the regional distribution of pirenzepine and carbamylcholine binding sites.

The binding capacities of the novel antagonist pirenzepine and the agonist carbamylcholine were examined autoradiographically to compare their abilities to reduce the binding of 1-[3H]quinuclidinyl benzilate ([3H]-1-QNB). This technique, which is applicable to any muscarinic ligand, permits a direct comparison between the binding of carbamylcholine and pirenzepine in the same assay. Analysis of the binding curves generated by standard scintillation counting of whole-brain slices indicated that the ligands bound heterogeneously to muscarinic receptors in the brain. Following apposition of slides to tritium-sensitive film, the binding profile for each ligand was examined visually and by microdensitometry. Regional analyses indicated that the agonist carbamylcholine displayed highest potency for thalamic nuclei, lower potency for cortical regions, and the lowest affinity for layers of the hippocampus. The M1-selective ligand pirenzepine displayed the highest potency for the dentate gyrus of the hippocampus, with lower inhibition levels in the cortex, and the lowest levels of inhibition found in the thalamus. The distribution of high affinity agonist sites was found to be distinct from the distribution of high-affinity antagonist binding sites. In a separate assay, the regional inhibition of pirenzepine and scopolamine was compared for the hippocampus and the forebrain. While scopolamine did not distinguish between muscarinic receptor sites in the hippocampus and cortex, pirenzepine inhibited [3H]-1-QNB labeling in the hippocampus significantly greater than in the cerebral cortex, providing additional evidence for the hypothesis that pirenzepine is a selective antagonist.

Animals↗
PubMed1987

Selectivity of pirenzepine in the central nervous system. II. Differential effects of pirenzepine and scopolamine on performance of a representational memory task.

The behavioral effects of the two muscarinic antagonists scopolamine and pirenzepine were examined using a representational memory task for rats in a T-maze. Rats were pretrained to a criterion of 100% correct responses for daily sessions of 10 paired-run trials. The training procedures eliminated all neophobic or wary responses, and response times were invariably short (less than 3 s). Following the initial training sessions, guide cannulae were surgically implanted bilaterally over the hippocampus of each animal. Following recovery from surgery, animals were injected with saline (0.5 microliter to each hippocampus), scopolamine hydrobromide (0.5 microliter of a 60 mg/ml solution (30 micrograms) to each side), or pirenzepine (0.5 microliter of a 69.1 mg/ml solution (34.6 micrograms) to each side) according to a fixed schedule. Saline injections aimed between the blades of the dorsal dentate gyrus failed to produce any change in the performance of the memory task. Initial doses of scopolamine, applied to the same area, produced a decrease in the percentage of correct responses as did the initial dose of pirenzepine. In contrast to pirenzepine, scopolamine also produced increases in response times even to the point of defaulted trials (response times greater than 90 s) in some animals following drug injections. Saline injections failed to produce significant impairments on the days following scopolamine injections, although animals receiving pirenzepine injections were still impaired on the two days immediately following the initial pirenzepine injection. Subsequent doses of pirenzepine were ineffective in producing an impairment of performance while scopolamine injections were less effective than the initial dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Selectivity of pirenzepine in the central nervous system. III. Differential effects of multiple pirenzepine and scopolamine administrations on muscarinic receptors as measured autoradiographically.

The effects of intrahippocampal injections of scopolamine and pirenzepine on muscarinic receptor binding were examined by quantitative autoradiographic techniques. Brain slices from animals which had received 7 injections of either scopolamine (n = 5) or pirenzepine (n = 5) over a 22-day injection schedule were compared with slices from 5 saline-injected controls for receptor binding to the whole slice and within selected regions of the brain as measured autoradiographically. The total number of receptors was determined from direct binding assays with 1-[3H]quinuclidinyl-benzilate ([3H]-1-QNB), while the binding of the selective ligands pirenzepine, carbamylcholine, and scopolamine was examined through inhibition studies. The data from the whole slices indicated that pirenzepine-treated animals contained more receptors for [3H]-1-QNB than either saline- or scopolamine-injected controls. Slices from the same animals also displayed a lower affinity for pirenzepine. Slices from scopolamine-injected animals revealed neither an increase in receptor number nor a decrease in antagonist affinity, although the binding of the agonist carbamylcholine was increased. Quantitative analysis of the autoradiograms generated from the slices indicated that the increase in receptor number for pirenzepine-injected animals was predominantly within the cerebral and cingulate cortices. The inhibition by pirenzepine was also lower in these areas in the same group of animals. Agonist inhibition was altered in the central layers of the cerebral cortex and in the pretectal area in scopolamine-treated animals. The results suggest separate mechanisms of drug action and adaptation for pirenzepine and scopolamine.

Animals↗
PubMed1986

Regional distribution of muscarinic receptors preferring gallamine in the rat brain.

The regional distribution of muscarinic receptors recognized by the antagonist gallamine was determined autoradiographically by the ability of gallamine to reduce the binding of [3H]quinuclidinyl benzilate in rat brain slices. The inhibition data obtained from indirect binding assays on whole slices indicated that gallamine distinguished at least two sites with differing affinities. Analysis using a two-site model gave Kh = 0.6 microM, K1 = 10 microM. The regions of highest and lowest affinity for gallamine were apparent qualitatively by visual inspection of the autoradiograms. A number of regions in coronal sections at three different levels were compared by microdensitometry. Gallamine possessed greater overall affinity for the diencephalon and brainstem than for the forebrain. Within the forebrain, the septal nucleus was unique in that it displayed high affinity for gallamine. Within the brainstem, the superior colliculus had the greatest proportion of sites with high affinity for gallamine. In general, the binding profile of gallamine was opposite to that of the antagonist pirenzepine and similar to that of the agonist carbachol, suggesting that gallamine is selective for M2 muscarinic receptors.

Animals↗