Akihiko Hamada

Differences in the applicability of the Easson-Stedman hypothesis to the α1- and α2-adrenergic effects of phenethylamines and imidazolines

The enantiomers of 2-(3,4, alpha-trihydroxybenzyl)imidazoline and the corresponding desoxy derivative, 2-(3,4-dihydroxybenzyl)imidazoline, were evaluated at alpha 1- and alpha 2-adrenergic receptors to test the applicability of the Easson-Stedman hypothesis to the imidazoline class of alpha-adrenergic agonists. A series of closely related phenethylamines was included for comparison. The Easson-Stedman hypothesis states that optically active adrenergic agonists possessing an asymmetric hydroxyl-substituted benzylic carbon atom will have the following relative potencies: R(-) greater than S(+) = desoxy. While the phenethylamines were found to adhere to the Easson-Stedman hypothesis at both alpha 1- and alpha 2-adrenergic receptors, the optically active imidazolines did not. These findings further support our previous observations that the phenethylamines and imidazolines may interact differently with alpha-adrenergic receptors.

Cupric bromide utilization in the synthesis of prostanoid intermediates

Abstract an effective, one-step procedure using CuBr 2 is reported for the introduction of a double bond into the prostanoid nucleus.

Dopaminergic agonists: comparative actions of amine and sulfonium analogues of dopamine

We have investigated the possibility that structural modifications of the sulfonium analogue of dopamine (4) would produce the same pattern of biological activity as structural modifications of dopamine. A series of methyl- tetralinyl -, and naphthalenylsulfonium analogues 5-7 were prepared and tested for their ability to inhibit the potassium-evoked release of [3H]acetylcholine from striatal slices. All compounds were tested under normal conditions and after depletion of dopamine stores with reserpine and alpha-methyl-p-tyrosine. The amine and sulfonium analogues 2-6 all showed direct agonist activity. The sulfonium analogue 7 produced, predominantly, indirect activity. In contrast to the amine analogues, chemical modifications of the sulfonium compounds produced little change in their dopamine agonist activity.

Alpha-adrenoceptor-mediated actions of optical isomers and desoxy analogs of catecholimidazoline and norepinephrine in human platelets: In vitro

Adrenoceptor-mediated effects of the enantiomers of optically active imidazoline, 2-(3,4,alpha-trihydroxybenzyl imidazoline (catecholimidazoline; CI), and norepinephrine (NE), and the corresponding desoxy derivatives, 2-(3,4-dihydroxybenzyl)imidazoline (desoxy-CI) and dopamine, have been investigated in human platelets. Differences between responsiveness of platelets from donor to donor were observed in the presence of the isomers and the desoxy analogs of NE and CI. In certain platelet preparations, all compounds gave concentration-dependent stimulatory responses, whereas in other preparations, only R(-)-NE and R(-)-CI were inducers of platelet aggregation and serotonin release. The rank order of stimulatory potencies (EC50; microM) for CI and NE was R(-)-NE (1.3) greater than R(-)-CI (7.5) greater than S(+)-NE (19) = S(+)-CI (20) = dopamine (22) greater than desoxy-CI (greater than 35). Unlike R(-)-CI, both S(+)-CI and desoxy-CI were either agonists or antagonists of human platelet function. In preparations unresponsive to the S(+)-isomers or desoxy analogs, the potencies (EC50) for R(-)-NE and R(-)-CI were 1.7 and 7.7 microM respectively. The corresponding inactive CIs [S(+)-CI and desoxy-CI] were inhibitors of both primary and secondary phases of aggregation and serotonin release responses to R(-)-CI and R(-)-NE, respectively. In contrast, the aggregation responses to ADP, arachidonic acid or U46619 were not blocked by S(+)-CI or desoxy CI. The rank order of inhibitory potencies for selected alpha-adrenoceptor agents against R(-)-NE was phentolamine greater than clonidine greater than desoxy-CI greater than S(+)-CI. Moreover, the relative inhibitory potencies of phentolamine and desoxy-CI against aggregation responses to R(-)-NE and R(-)-CI, respectively, were the same. These results suggest that the enantiomers and desoxy derivatives of CI and NE mediate their effects in human platelets by an interaction with alpha-adrenoceptors; catecholamines and imidazolines interact with the same alpha-adrenoceptors in human platelets; the stereochemical requirements of both chemical classes for stimulatory activity in human platelets adhere to the Easson-Stedman hypothesis in this alpha 2-adrenoceptor system; and desoxy-CI possessed the highest potency as an antagonist of alpha-adrenoceptors which suggests that the hydroxy group at the benzylic carbon atom of these imidazolines may not be required for maximal binding to adrenoceptors in platelets.

Paradoxical Effects of Isothiocyanate Analog of Tolazoline on Rat Aorta and Human Platelets

The isothiocyanate analog (IBI) of tolazoline produced contraction of the rat aortic strip, with an ED50 value of 1.63 x 10(-5) M. The maximum contraction of the analog was nearly equal to that of tolazoline or phenylephrine. At 27 degrees C the tissue reactivity of phenylephrine and IBI was similar. When compared at equiactive concentrations, the total duration of contraction of IBI was three times longer than that of tolazoline. Thus, the longer duration of action of IBI may be attributed to the S=C=N group substitution of the molecule. IBI at 10(-6) M shifted the dose-response curve of phenylephrine to the right with reduction in maxima. Phentolamine and other alpha 1 or alpha 2 adrenoceptor blockers failed to block the responses of IBI in aorta, whereas verapamil or nifedipine blocked the response significantly. It appears that IBI is acting through calcium-channel-sensitive or calcium-receptor-related mechanism(s). In aspirin-treated platelets from human plasma, a distinct phase of aggregation induced by epinephrine can be blocked by IBI with KB of 2 x 10(-5) M. This indicates a small but selective alpha 2 related action of IBI. The aggregation induced by ADP or second component of aggregation induced by epinephrine were also blocked by IBI at concentrations comparable to that of the alpha 2-adrenoceptor-mediated response. This indicates a lack of specificity of IBI in differentiating various phases of aggregation. Therefore, as compared to tolazoline, IBI presents an interesting paradox in its interaction with various receptors or mechanisms in the vascular tissue and platelets.

Interaction of enantiomers of hydroxy tolazoline with adrenoceptors

SummaryAdrenoceptor-mediated effects of the enantiomers of hydroxytolazoline and tolazoline (i. e., desoxy derivative) have been investigated in vitro. The enantiomers and tolazoline were partial agonists of postjunctional α1-adrenoceptors in rat aorta. The rank order of potencies of the compounds in this system was as follows: tolazoline > R(−)-hydroxytolazoline > S(+)-hydroxytolazoline. The efficacy of R(−)-hydroxytolazoline was higher than that of tolazoline, though its affinity for the receptor was less. The KB values for prazosin against these agonists were nearly equal, which indicated that these imidazolines activate the same type of receptor in rat aorta. The S(+)-isomer, however, produced both a prazosin sensitive and resistant component of the response. The interactions of the derivatives with presynaptic α2-adrenoceptors were studied in field-stimulated myenteric plexus-longitudinal muscle of guinea-pig ileum. These substances were blockers at presynaptic α2-adrenoceptors. Based on KB values, the order of affinity in this system was as follows: tolazoline > S(+)isomer ≥ R(−)-isomer. β-Adrenoceptor mediated activity was quantitated in guinea-pig and rat atria. R(−)-hydroxytolazoline lacked chronotropic effects either in guinea pig or rat atria. At 3 × 10−4 M the isomer did not antagonize the effect of isoproterenol in the atria. On the other hand, S(+)-hydroxytolazoline produced a variable chronotropic effect in guinea-pig atria, but failled to show any significant activity in rat atria. Thus, the β-adrenoceptor mediated action appears to be insignificant. Steric aspects of α-adrenoceptor mediated events are discussed.

Halogen-substituted trimetoquinol analogs as thromboxane A2 receptor antagonists in platelets and aorta.

Trimetoquinol (TMQ) is a non-prostanoid compound that blocks prostaglandin H2/thromboxane A2 (TXA2) receptor-mediated responses initiated by a prostaglandin (PG) H2 analog, U46619, in human platelets and rat aorta. Ring fluorine-substituted TMQ analogs selectively antagonized PG-dependent human platelet activation induced by U46619, arachidonic acid, collagen, ADP or epinephrine; and were about 300-fold less potent as inhibitors of PG-independent responses mediated by thrombin or bacterial phospholipase C. For each inducer of the PG-dependent pathway, the rank order of inhibitory potency was identical (TMQ > 8-fluoro-TMQ > 5-fluoro- TMQ). Iodine substitution yielded a similar rank order of antagonism against U46619-induced platelet activation (TMQ > 8-iodo-TMQ > 5-iodo-TMQ), and all TMQ analogs inhibited platelet aggregation in whole blood as well as in platelet-rich plasma. Inhibition of specific [3H]SQ 29,548 binding by TMQ analogs was highly correlated with inhibition of functional responses to U46619. Radioligand binding experiments using TMQ analogs with rat platelets showed no interspecies difference in comparison with human platelets. The rank order of inhibitory potencies for the fluorinated (but not iodinated) TMQ analogs changed in rat thoracic aorta with 8-fluoro-TMQ > TMQ > or = 5-fluoro-TMQ as antagonists of U46619-induced vascular contraction. These findings demonstrate that the primary mechanism of antiplatelet action of TMQ analogs is related to a blockade of TXA2 receptor sites, and ring-halogenated TMQ analogs distinguish between TXA2-mediated functional responses in vascular smooth muscle and platelets.

Structure-activity studies of new imidazolines on adrenoceptors of rat aorta and human platelets

SummaryPotencies of new aromatic substituted fluoro or iodo analogues of catecholimidazolines on functional responses in rat aorta (α1) and platelets (α2) were quantified.(1) When compared either on the basis of EC50 or the dissociation constant (KA), 5-fluorocatecholimidazoline was as potent as the reference α1-adrenoceptor agonist, phenylephrine in the vascular tissue. The maximum contraction of aorta produced by the fluoro analogue was, however, 17% higher than that of phenylephrine. The time required for 1/2 relaxation of the tissue after 5-fluoro hydroxy imidazoline was at least twice as long as that of the phenylephrine. The catechol moiety as well as fluorine substitution at the critical 5-position of the aromatic ring is essential for higher α1 adrenoceptor-mediated potency. (2) As compared to the fluoro analogues, the adrenoceptor-mediated potencies of iodo-analogues were relatively weak on vascular tissue. Naphazoline and its analogues were partial agonists on vascular tissue with dissociation constants which ranged from 110 to 2600 nmol/l. (3) Imidazole analogues were generally less potent agonist than the imidazolines by one order of magnitude. (4) The vascular effects of all agonists were competitively blocked by prazosin with KB values which ranged from 0.04 to 0.48 nmol/l. Since the variation in KB values were within normal limits, the action of new imidazolines on rat aorta appears to be mediated mainly by the activation of the α1-adrenoceptor. Prazosin 10 nmol/l abolished the vascular response of some partial agonists. This indicates a slightly different mode of interaction of agonists with the transduction process. (5) Carbon 4-substituted imidazolines produced little or no α1 adrenoceptor-mediated intrinsic activity, but competitive receptor blocking potency was comparable to that of phentolamine. (6) Medetomidine was a partial agonist on the rat aorta with a KA of 260 nmol/l. When investigated as a blocker, the KB of medetomidine against phenylephrine was approximately 5600 nmol/l. The variation in the latter value was high. (7) In acetylsalicylic acid-treated human platelets, the α2-adrenoceptor-mediated aggregatory effect of all fluoro analogues was weak. lodo or naphazoline analogues did not initiate platelet aggregation but blocked the aggregation induced by epinephrine. The affinity of naphazoline for the α2-adrenoceptor was 1100 nmol/l. The IC50 of medetomidine for platelet anti-aggregatory effect was 3300 nmol/l, which compares favorably with other imidazoline type of blockes of platelet aggregation. (8) Sympathomimetic vasoconstrictor actions and platelet aggregation effects of these compounds can be dissociated. Some vasoconstrictors were antiaggregatory. The structure-activity relationships of the two receptor systems, namely rat aorta (α1) and platelets (α2), are discussed.

Effects of benzylic hydroxyl substitution on the α-adrenoceptor blocking activity of tolazoline

Abstract The R(−)- and S(+)-enantiomers of α-hydroxytolazoline, the benzylic hydroxy-substiuted derivative of the α-adrenoceptor antagonist, tolazoline, were evaluated at α1- and α2-adrenoceptors in canine saphenous vein. Benzylic hydroxyl substitution of tolazoline in either the R(−) or S(+) configuration significantly decreased affinity at both α1- and α2-adrenoceptors. Differences in affinity between the R(−)- and S(+)-enantiomers were small, which is characteristic of imidazolines, but in marked contrast to phenethylamines where enantiomeric differences are large. The rank order of affinities at α1- and α2-adrenoceptors is tolazoline > S(+)-α-hydroxytolazoline = R(−)-α-hydroxytolazoline, which is different from that order predicted by the Easson-Stedman hypothesis (i.e., R(−) > S(+) = desoxy). The findings support our contention that phenethylamines and imidazolines interact differently with α-adrenoceptors.