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A C MacKinnon

Publications and source records attributed to A C MacKinnon.

25 records · Page 2Linked to original sources
PubMed1990

Affinity of 2-(tetrahydroisoquinolin-2-ylmethyl)- and 2-(isoindolin-2-ylmethyl)imidazolines for alpha-adrenoceptors. Differential affinity of imidazolines for the [3H]idazoxan-labeled alpha 2-adrenoceptor vs the [3H]yohimbine-labeled site.

A series of 2-(tetrahydroisoquinolin-2-ylmethyl)- and 2-(isoindolin-2-ylmethyl)imidazolines were prepared and tested for alpha 1- and alpha 2-adrenoceptor affinity with radioligand binding. Several compounds, 5-fluoro-(5h), 5-chloro-(5j), 5,8-dimethoxy- (5r), and 5,8-dimethoxy- (5r),1-methyl- (5s) 2-(tetrahydroisoquinolin-2- ylmethyl)imidazoline, were found to be selective alpha 2-adrenoceptor ligands on the basis of displacement of [3H]yohimbine from rat cerebral cortical membranes. One compound, 2-[(8-chloro tetrahydroisoquinolin-2-yl)methyl]imidazoline (5m), showed a 36-fold difference in affinity for the [3H]idazoxan-labeled alpha 2-adrenoceptor relative to the [3H]yohimbine-labeled site, which may be evidence for alpha 2-adrenoceptor subtypes.

Animals↗
PubMed1990

1,9-Alkano-bridged 2,3,4,5-tetrahydro-1H-3-benzazepines with affinity for the alpha 2-adrenoceptor and the 5-HT1A receptor.

A number of 1,9-alkano-bridged 2,3,4,5-tetrahydro-1H-3-benzazepines were prepared and evaluated for 5-HT1A receptor and alpha 2-adrenoceptor affinity by using radioligand receptor binding techniques. Several compounds displayed 5-HT1A receptor affinity comparable to, or greater than, the known 5-HT1A ligand buspirone. The highest affinity 5-HT1A receptor ligands were N-alkyl-, N-allyl-5-chloro-, and 5-methoxy-1,2,3,4,8,9,10,10a-octahydronaphth[1,8-cd]azapines (4c, 4m, 4n), which had pKi values of 7.9-8.1. The S enantiomer of 4c had a higher affinity for the 5-HT1A receptor than the corresponding R isomer (pKi of 8.2 for (S)-4c vs 7.7 for (R)-4c). These compounds had a relatively low affinity for the alpha 2-adrenoceptor (pKi of 7 or less). On the other hand, the closely related 5-chloro-2-methyl-2,3,4,8,9,9a-hexahydro-1H-indeno[1,7-cd]azepine (3b) had high affinity for both the alpha 2-adrenoceptor (pKi = 8.1) and 5-HT1A receptor (pKi = 7.6). These results indicate that the two receptors may share common recognition sites.

Animals↗
PubMed1990

Heterogeneity of alpha 2-adrenoceptors in rat cortex but not human platelets can be defined by 8-OH-DPAT, RU 24969 and methysergide.

1. Saturation experiments indicated that [3H]-yohimbine binding was specific, saturable and labelled a single population of sites in rat cerebral cortex (Kd 5.3 +/- 0.9 nM, Bmax 121 +/- 10 fmol mg-1 protein) and human platelets (Kd 0.7 +/- 0.1 nM, Bmax 152 +/- 10 fmol mg-1 protein). 2. The alpha 2-adrenoceptor antagonists, yohimbine, rauwolscine, WY 26703, idazoxan and BDF 6143 displaced [3H]-yohimbine binding to each tissue in a simple manner, with high affinity and Hill slopes close to unity. 3. The alpha 1-adrenoceptor agonist, oxymetazoline and the antagonist prazosin inhibited the binding of [3H]-yohimbine to rat in a complex manner consistent with an interaction at more than one site. However, indoramin and WB 4101 only appeared to interact with one site. In contrast, in human platelets, all antagonists gave rise to monophasic displacement curves with Hill slopes close to unity suggesting a single site of interaction. 4. The 5-hydroxytryptamine (5-HT) receptor ligands, 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), RU 24969, and methysergide inhibited the binding of [3H]-yohimbine to rat cortex with high and low affinity, consistent with an interaction with two populations of binding sites. However, inhibition of [3H]-yohimbine binding to human platelets suggested a single site of interaction. The low affinity of 5-HT, 5-carboxyamidotryptamine (5-CT) and dipropyl-5-CT indicated that [3H]-yohimbine was not labelling a 5-HT1-like site in rat cortex. 5. The ability of 8-OH-DPAT, RU 24969 and methysergide in addition to prazosin and oxymetazoline to differentiate [3H]-yohimbine binding provides additional pharmacological evidence for heterogeneity within rat cortical alpha 2-adrenoceptors. However, if the two sites in rat cortex that are differentiated by the 5-HT ligands represent (alpha 2A- and alpha 2B-adrenoceptor subtypes as defined by prazosin and oxymetazoline, then they do not correspond to the population of sites in human platelets. As receptor classification should be linked to affinity of drugs rather than tissue distribution, the current classification of alpha 2-adrenoceptor subtypes does not appear to be satisfactory.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1990

Alpha 2-adrenoceptor subtypes and imidazoline-like binding sites in the rat brain.

1. The binding of [3H]-yohimbine and [3H]-idazoxan to rat cortex and hippocampus is rapid, reversible and of high affinity. Saturation data indicate that a single population of binding sites exist for [3H]-yohimbine in the cortex (Bmax 121 +/- 10 fmol mg-1, protein; Kd 5.2 +/- 0.9 nM) and hippocampus (Bmax 72 +/- 6 fmol mg-1 protein; Kd 5.8 +/- 0.7 nM). [3H]-idazoxan labels one site in the cortex (Bmax 87 +/- 8 fmol mg-1 protein; Kd 4.1 +/- 0.9 nM) and hippocampus (Bmax 30 +/- 6 fmol mg-1 protein; Kd 3.5 +/- 0.5 nM), when 3 microM phentolamine is used to define non-specific binding. A second distinct [3H]-idazoxan binding site (Bmax 110 +/- 21 fmol mg-1 protein; Kd 3.6 +/- 0.07 nM) is identified in rat cortex if 0.3 microM cirazoline is used to define non-specific binding and 3 microM yohimbine is included to prevent binding to alpha 2-adrenoceptors. 2. Displacement studies indicate that the alpha 1-adrenoceptor antagonist prazosin and the 5-HT1 ligands 8-OH-DPAT, RU 24969 and methysergide differentiate [3H]-yohimbine binding into two components; a high and low affinity site. In contrast the displacement of [3H]-idazoxan by each ligand was monophasic. 3. The affinities of 8-OH-DPAT, RU 24969 and methysergide determined against [3H]-idazoxan binding to the cortex and hippocampus correlate significantly with the binding site displaying low affinity for prazosin and previously designated alpha 2A. In contrast, a poor correlation exists for the high affinity site for prazosin designated alpha 2B. 4. [3H]-idazoxan, in the presence of 3 microM yohimbine, labels a site that displays high affinity towards cirazoline, naphazoline and guanabenz, but low affinity towards clonidine, p-aminoclonidine, adrenaline, noradrenaline and the alpha 2-adrenoceptor antagonists yohimbine, rauwolscine, WY 26703 and BDF 6143. 5. The results of this study indicate that [3H]-yohimbine labels two sites; the alpha 2A- and alpha 2B-adrenoceptors whereas [3H]-idazoxan labels an alpha 2-adrenoceptor with a profile consistent with the alpha 2A-adrenoceptor subtype. In addition, [3H]-idazoxan labels an imidazoline binding site in the rat cortex that is pharmacologically distinct from alpha 2-adrenoceptors. The low affinity of clonidine and p-aminoclonidine indicates that the imidazoline-like binding site in rat cortex is different from the site labelled by [3H]-clonidine and [3H]-p-aminoclonidine in human, rat and bovine brain stem, providing evidence of potential heterogeneity within this class of binding sites.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1989

The alpha 2-adrenoceptor antagonist SK&F 104078 has high affinity for 5-HT1A and 5-HT2 receptors.

The affinity of SK&F 104078, a putative selective postjunctional alpha 2-adrenoceptor antagonist, was determined at 5-HT1A and 5-HT2 receptors in rat brain. SK&F 104078 had moderate affinity towards alpha 2-adrenoceptors (pKi 6.7) but displayed higher affinity at 5-HT1A (pKi 8.1) and 5-HT2 (pKi 7.6) receptors. If SK&F 104078 is used in functional studies to define heterogeneity within of alpha 2-adrenoceptors, care must be taken to define the role of 5-HT1A and 5-HT2 receptors in the response being measured.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1989

[3H]-idazoxan binds with high affinity to two sites on hamster adipocytes: an alpha 2-adrenoceptor and a non-adrenoceptor site.

1. [3H]-idazoxan labels a single population of high affinity sites (Kd 2.26 +/- 0.02 nM; Bmax 372 +/- 25 fmol mg-1 protein) in hamster adipocyte membranes. In the presence of 1 microM yohimbine to preclude binding to alpha 2-adrenoceptors, the density of [3H]-idazoxan binding sites was reduced (287 +/- 18 fmol mg-1 protein) without an apparent decrease in the affinity (Kd 2.19 +/- 0.24 nM) of the radioligand. 2. Displacement studies indicate that alpha-adrenoceptor ligands with an imidazoline side chain completely inhibit [3H]-idazoxan binding to hamster adipocyte membranes; in contrast, the alpha 2-adrenoceptor antagonists yohimbine, rauwolscine, BDF 6143 and phentolamine inhibited only 20-30% of the specific binding with affinity values consistent with an interaction at alpha 2-adrenoceptors. 3. The low potency of noradrenaline and adrenaline in displacing [3H]-idazoxan binding to the second site on hamster adipocyte membranes indicates that it is unlikely that this site is a type of adrenoceptor. 4. These results suggest that [3H]-idazoxan binds with high affinity to two sites in hamster adipocytes: an alpha 2-adrenoceptor and a non-adrenoceptor imidazoline site.

Adipose Tissue↗