2-propyl-4-5-5a-6-7-11b-hexahydro-3-thia-5-azacyclopent-1-ena(c)phenanthrene-9-10-diol and adrogolide-hydrochloride

The purpose of this study was to evaluate the feasibility of intrapulmonary delivery of ABT-431, a selective D1 receptor agonist. Following intratracheal instillation of the drug solution, the lung bioavailability was found to be approximately 75% in dogs. An aerosol suspension formulation was then developed by dispersing the drug in tetrafluoroethane, HFC-134a, with the aid of poloxamer 124 and vitamin E. This ABT-431 MDI aerosol formulation showed about 40% of the particles emitted from the valve and actuator system to be under 5 microm in diameter. Also, the primary package (15 mL aluminum container, DF10/ACT-150 valve, and Micron-4-actuator with the orifice 0.4 mm) was satisfactory for accurate and reproducible dosimetry. Using tracheostomized beagle dogs, the C(max) following tracheal administration of 5 mg aerosolized ABT-431 was found to be 13.3+/-0.9 ng ml(-1) and the AUC(0-24) was estimated at 33.2+/-10.6 h ng ml(-1). The lung bioavailability of the aerosolized drug was 34% compared to intravenous injection in dogs. In humans, results from a single rising dose study demonstrated that rapid absorption of ABT-431 following oral inhalation administration resulted in a dose-dependent increase in the area under the plasma-time curve at dosage levels between 3.3 and 13.2 mg. There is a possibility of up to 25% absorption of the drug from human lung. Thus, pulmonary bioavailability of ABT-431 is significantly greater than that of oral administration. Also, these findings suggest that small and lipophilic compounds, especially with hepatic first pass effect, may be effectively delivered systemically using oral inhalation aerosols.

Topics: Absorption; Adult; Aerosol Propellants; Aerosols; Animals; Area Under Curve; Biological Availability; Dogs; Dopamine Agonists; Double-Blind Method; Humans; Injections, Intravenous; Lung; Male; Nebulizers and Vaporizers; Particle Size; Prodrugs; Pyridines; Quinolones; Receptors, Dopamine D1; Tetrahydronaphthalenes; Thiophenes

(-)-Trans 9,10-hydroxy-2-propyl-4,5,5a,6,7,11b-hexahydro-3-thia-5- azacyclopent-1-ena[c]phenanthrene hydrochloride (A-86929) is a potent and selective full agonist at the dopamine (DA) D1-like receptor. Judging by its binding affinities to the D1 and D2 classes of receptors, the compound is approximately 20-fold D1 receptor-selective, whereas relative potencies based on functional in vitro assays indicate that A-86929 is greater than 400-fold D1-selective. A-86929 has moderate to weak (Ki > 1 microM) affinity at other monoaminergic and peptidergic receptors, at ion channels and at monoamine uptake sites. The catechol of A-86929 was bis-acetylated to produce the prodrug, (-)-trans 9,10-acetoxy-2-propyl-4,5,5a,6,7,11-b-hexahydro-3-thia- 5-azacyclopent-1-ena[c]phenanthrene hydrochloride (ABT-431), which is more chemically stable yet is rapidly converted to the parent compound with a half-life of less than 1 min in plasma. Both A-86929 and ABT-431 produced contralateral rotation in rats bearing unilateral 6-hydroxydopamine lesions, with ED50 values of 0.24 mumol/kg s.c. and 0.54 mumol/kg s.c., respectively. A-86929 and ABT-431 improved behavioral disability scores and increased locomotor activity in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned marmoset model of Parkinson's disease in a dose-dependent manner (the minimum effective dose was 0.10 mumol/kg s.c.). When administered three times daily for 30 consecutive days to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned marmosets, A-86929 significantly improved disability scores throughout the duration of the study. Current Parkinson's disease therapy includes L-dopa, which stimulates both classes of DA receptors by virtue of its conversion to DA in vivo, and direct-acting D2-selective agonists. Stimulation of the D2 receptor, which is associated with all current DA agonist-based therapies, may contribute to their dose-limiting side effects. An agent such as A-86929 (or its prodrug ABT-431), which selectively stimulates the D1 receptor, may represent a novel mechanism for Parkinson's disease therapy with the potential for an improved side-effect profile and, consequently, improved patient compliance.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Antiparkinson Agents; Behavior, Animal; Callithrix; CHO Cells; Corpus Striatum; Cricetinae; Disease Models, Animal; Dopamine Agonists; Dose-Response Relationship, Drug; Female; Fishes; Humans; Kinetics; Male; Mice; Parkinson Disease, Secondary; Prodrugs; Pyridines; Quinolones; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1; Tetrahydronaphthalenes; Thiophenes

A-86929 ((-)-trans-9,10-dihydroxy-2-propyl-4,5,5a,6,7,11b-hexahydro-3- thia-5-azacyclopent-1-ena[c]phenanthrene) is a potent and selective full agonist at the dopamine D1 receptor. Both A-86929 and ABT-431 ((-)-trans-9,10-diacetyloxy-2-propyl-4,5,5a,6,7,11b- hexahydro-3-thia-5-azacyclopent-1-ena[c]phenanthrene hydrochloride), the diacetyl prodrug derivative of A-86929, were evaluated for their effects on behavioral excitability in rodents. In rats, A-86929 produced a dose-dependent increase in locomotor activity that was attenuated by the selective dopamine D1 receptor antagonist, SCH 23390, as well as by higher doses of the dopamine D2 receptor antagonist, haloperidol. Repeated administration of A-86929 over 6 days produced hyperactivity which did not change in magnitude across days. Acute administration of A-86929 and ABT-431 to mice produced behavioral seizure activity, with ED50 values of 7.1 and 2.7 mumol/kg, s.c., respectively, that was blocked by SCH 23390. Young rats (35-37 days) exhibited behavioral seizures following A-86929 and ABT-431 treatment (ED50 = 34.2 and 35.6 mumol/kg, s.c., respectively), but at doses higher than those required in mice. Moreover, adult rats (3 months) were less sensitive (ED50 = 345 mumol/kg, s.c.) to A-86929-induced seizures than young rats. Comparison of the ED50 values that produced behavioral seizure activity in rats with those previously established to produce contralateral rotation (ED50 = 0.24 mumol/kg, s.c.) in 6-hydroxydopamine-lesioned rat indicates that a significant dose separation exists between these two properties of A-86929.

Topics: Animals; Behavior, Animal; Benzazepines; Dopamine Agonists; Dopamine Antagonists; Dose-Response Relationship, Drug; Male; Mice; Motor Activity; Oxidopamine; Prodrugs; Pyridines; Quinolones; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1; Seizures; Sympathectomy, Chemical; Tetrahydronaphthalenes; Thiophenes

Topics: Acetylation; Animals; Behavior, Animal; Drug Administration Schedule; Humans; Prodrugs; Protein Precursors; Pyridines; Quinolones; Rats; Receptors, Dopamine D1; Receptors, Dopamine D2; Structure-Activity Relationship; Tetrahydronaphthalenes; Thiophenes