Beta-adrenergic Partial Agonists Research Articles

Transition of drug receptor mechanisms

It is generally accepted that the agonists, full agonist and partial agonist, interact with the same receptors according to the classical receptor mechanisms. We tried to modify the drug receptor mechanisms in muscarinic cholinoceptors, alpha 1-adrenoceptors and beta-adrenoceptors. In the muscarinic cholinoceptor, there are two subtypes of M3-cholinoceptors, propylbenzilylcholine mustard (PrBCM)-sensitive receptors and PrBCM-resistant ones. The full agonists contract the longitudinal muscle through the interaction of two cholinoceptors, PrBCM-sensitive and-resistant ones, while the partial agonists produce the contraction through only the activation of PrBCM-sensitive ones. Upon activation PrBCM-sensitive receptors may use cytosolic Ca2+ more effectively than PrBCM-resistant receptors. In the alpha 1-adrenoceptor, the full agonist induces contraction through both alpha 1A and alpha 1B subtypes and the partial agonist through only alpha 1A subtype. The adrenoceptors activated by full agonist may be partly different from that by partial agonist in the arteries. In both the common iliac artery and thoracic aorta treated with the irreversible antagonist, phenoxybenzamine the slopes of schild plots of the results obtained from an antagonism between full agonist (phenylephrine) and alpha 1A-selective competitive antagonist (WB4101) equal to 1, suggesting that phenoxybenzamine preferably interacts with alpha 1B subtype. In the beta-adrenoceptor, the pD2-values of the partial agonists obtained from the concentration-response curves are significantly different from their pA2-values against full agonist (isoprenaline). The Scatchard plot of the specific [3H]befunolol (the partial agonist) binding showed two affinity sites of the receptors in the absence of Gpp(NH)p but the low affinity site was reduced while the high affinity site was not affected in the presence of Gpp(NH) p. The beta-adrenergic partial agonists are able to discriminate these two different binding sites of the beta-adrenoceptors. Our results suggest that the receptors activated by full agonists are partly different from those by partial agonists in muscarinic cholinoceptors, alpha 1- and beta-adrenoceptors, and that the irreversible antagonist can discriminate between the sites interact with full agonists and those with partial agonists in muscarinic cholinoceptors and alpha 1-adrenoceptors.

Interactions of R(+)- and S(-)-isomers of beta-adrenergic partial agonists with the high affinity site of beta-adrenoceptors

Interactions of R(+)- and S(-)-isomers of beta-adrenergic partial agonists with the high affinity site of beta-adrenoceptors

P-327 - Stereoselectivity in beta-adrenoceptor of beta-adrenergic partial agonists, befunolol and carteolol! isolated rabbit ciliary body and guinea-pig taenia caecum.

P-327 - Stereoselectivity in beta-adrenoceptor of beta-adrenergic partial agonists, befunolol and carteolol! isolated rabbit ciliary body and guinea-pig taenia caecum.

Stereoselectivity in beta-adrenomimetic and beta-adrenolytic actions of carteolol, a beta-adrenoceptor blocker with intrinsic sympathomimetic action in guinea-pig taenia caecum

1. 1. The beta-adrenomimetic and beta-adrenolytic activities of S(−) and R(+) isomers of carteolol, a beta-adrenergic partial agonist (a beta-adrenoceptor blocker with intrinsic sympathomimetic action) were tested in the guinea-pig taenia caecum. 2. 2. The beta-adrenoceptor blocking activities (pA 2 values) of S(−) and R(+) isomers of carteolol were significantly larger than the corresponding beta-adrenomimetic activities (pD 2 values), supporting our views that beta-adrenoceptors contain two different binding sites; high and low affinity sites. 3. 3. In beta-adrenoceptor blocking action S(−) carteolol was about 10 times as potent as R(+) carteolol, while beta-adrenomimetic action of S(−) carteolol was about 2 times as potent as that of R(+) carteolol. Further, intrinsic activity for S(−) carteolol was slightly but significantly larger than that for R(+) carteolol. 4. 4. These results suggest that the binding site for competitive antagonism between S(−) isoprenaline and S(−), R(+) and RS(±) carteolol is more stereoselective than the binding site to induce beta-adrenomimetic action.

Effects of the Novel β-Adrenergic Partial Agonist Alifedrine on Cardiac Performance in Dogs with Acute Ischemic Left Ventricular Failure

Acute ischemic left ventricular failure was induced in dogs by coronary embolization with plastic microspheres, resulting in reduced cardiac output (CO), increased left ventricular end-diastolic pressure (LVEDP), pulmonary capillary pressure (PCP), and total peripheral resistance (TPR). Intravenous (i.v.) administration of alifedrine, a beta-adrenergic partial agonist (0.3 mg/kg as bolus and 0.3 mg/kg/h as infusion), significantly improved performance of the failing heart. Left ventricular contractility was increased up to 50%, heart rate (HR) up to 28%, and CO up to 30%. LVEDP, PCP, and TPR were markedly decreased. Myocardial oxygen consumption was increased only to a minor degree despite the positive inotropic effect; coronary flow was augmented up to 26%. Thus, alifedrine in this model markedly improved left ventricular function by balanced stimulation of the myocardium and reduction of pre- and afterload.

Binding of [3H]befunolol to beta-adrenoceptors in cardiac muscles of fetal and neonatal rat.

Characterization of beta-adrenoceptors was studied in heart muscles of rat fetus and neonate. The results of binding assay with [3H]befunolol, a beta-adrenergic partial agonist, to membrane fractions from rat heart muscles indicate that beta-adrenoceptors contain two different affinity sites. In the presence of 5'-guanylylimidodiphosphate, the low affinity site was reduced, while the high affinity site was not affected. The dissociation constants for both sites did not change during pre- and post-natal development. But the maximum binding sites for both sites decreased slightly but significantly (p less than 0.05) during development. A 10-fold decrease in norepinephrine sensitivity and isoprenaline sensitivity during pre- and post-natal development was not explained by the slight decrease in the maximum binding sites.

A derivative of befunolol, BFE-55, interacts with only the high affinity sites in beta-adrenoceptors.

The effect of BFE-55, a derivative of befunolol (a beta-adrenergic partial agonist) on specific [3H]befunolol binding to a microsomal fraction from the guinea pig taenia caecum was tested. A Scatchard plot of specific [3H]befunolol binding in the absence of BFE-55 was concave, suggesting an existence of high and low affinity sites in beta-adrenoceptors. In contrast, the Scatchard plot of data in the presence of BFE-55 (3 X 10(-7) M) was straight. In the presence of BFE-55, the high affinity sites disappeared and the low affinity site was unaffected. In the absence and presence of BFE-55 there was no difference between the pKD values or Bmax values at the low affinity site. These findings indicate that BFE-55 interacts with only the high affinity sites in beta-adrenoceptors.

Interactions of befunolol, a beta-adrenergic partial agonist, and its derivatives with high and low affinity sites in beta-adrenoceptors.

Modes of action of befunolol and its derivatives were tested in guinea pig isolated taenia caecum. The pA2-values of BFE-60 (befunolol), -61 and -69 against isoprenaline, which measures interactions with the high affinity sites on beta-adrenoceptors, were significantly larger than their pD2-values, which were equal to their pA2-values against carteolol. Carteolol is a beta-adrenergic partial agonist with higher intrinsic activity, to which the response results from interaction with low affinity sites. These results suggest that BFE-60, -61 and -69 discriminate the high and low affinity sites on beta-adrenoceptors. The pA2-values of BFE-37, -41, -47 and -72 against isoprenaline were, however, equal to their pD2-values and pA2-values against carteolol. These drugs seem to have little or no ability to discriminate between the high and low affinity sites. BFE-55 antagonized isoprenaline but not carteolol suggesting that BFE-55 interacted with only the high affinity sites.

A Beta-Adrenergic Partial Agonist (Befunolol) Discriminates Two Different Affinity Sites

Interactions of beta-adrenergic partial agonists with the beta-adre- noceptor were studied in isolated guinea-pig taenia caecum. The competitive inhibition curve for specific binding of a high concentration (50 nM) of [3H]-befunolol by befunolol showed a biphasic shape, although the curve for specific binding of a low concentration (1 nM) was monophasic. All the competitive inhibition curves for specific binding of [3H]-befunolol (1 nM and 50 nM) by iso- prenaline and propranolol showed monophasic shapes. These results suggest that befunolol may be able to discriminate two different binding sites of the beta- adrenoceptor: the high affinity site and the low affinity site.

S5D15107) - Agonist site and antagonist site for beta-adrenergic partial agonist.

S5D15107) - Agonist site and antagonist site for beta-adrenergic partial agonist.

O-32) - Interactions of some beta-adrenergic partial agonists with their receptor in guinea-pig taenia caecum and tracheal smooth muscle

O-32) - Interactions of some beta-adrenergic partial agonists with their receptor in guinea-pig taenia caecum and tracheal smooth muscle

Interactions of Some Partial Agonists with Beta-Adrenoceptor in the Isolated Taenia Caecum and Tracheal Smooth Muscle of Guinea Pig

The indexes for agonistic activity (pD2 values) and for antagonistic activity (pA2 values) of some beta-adrenergic partial agonists were estimated in the isolated taenia caecum and tracheal preparation of guinea pig. The pKj values, negative log of dissociation constants, were aiso estimated by photoinactivation of the beta-adreneoceptor in the taenia caecum. The pD2 values of the partial agonists were significantly different from their pA2 values, but equal to their pKi values. If the partial agonists interacted with one site in their receptor, the pD2 values would be equal to the pA2 values because the partial agonists had little receptor reserve. These results suggest that the properties of the binding site for agonistic action were different from those for antagonistic action.

A possible mechanism of action of a beta-adrenergic partial agonist (carteolol) in guinea pig taenia caecum.

Carteolol, 5-(3-tert-butylamino-2-hydroxy)propoxy-3, 4-dihydrocarbostyril hydrochloride was found to be a beta-adrenergic partial agonist in the taenia caecum of guinea pig. Concentration response curves of carteolol and isoprenaline were parallelly shifted by propranolol (10(-7) M) suggesting that site of action of both the drugs was the same beta-adrenoceptor. The pD2-values of carteolol obtained from the concentration action curves in mechanical response and increase of tissue concentration of cyclic AMP were significantly different from its pA2-value against isoprenaline and its pKi-value (negative log of its apparent dissociation constant). A possible explanation of our observation would seem to be as follows. Carteolol and isopranaline interact with the same beta-adrenoceptor where there may be two different sites: a binding site for agonist and binding site for antagonist.