Adrogolide HCl (ABT‐431; DAS‐431), a Prodrug of the Dopamine D₁ Receptor Agonist, A‐86929: Preclinical Pharmacology and Clinical Data

Abstract

Adrogolide (ABT-431; DAS-431) is a chemically stable prodrug that is converted rapidly (<1 min) in plasma to A-86929, a full agonist at dopamine D 1 receptors. In in vitro functional assays, A-86929 is over 400 times more selective for dopamine D 1 than D 2 receptors. In rats with a unilateral loss of striatal dopamine, A-86929 produces contralateral rotations that are inhibited by dopamine D 1 but not by dopamine D 2 receptor antagonists. Adrogolide improves behavioral disability and locomotor activity scores in MPTPlesioned marmosets, a model of Parkinson's disease (PD), and shows no tolerance upon repeated dosing for 28 days.In PD patients, intravenous (i.v.) adrogolide has antiparkinson efficacy equivalent to that of L-DOPA with a tendency towards a reduced liability to induce dyskinesia. The adverse events associated with its use were of mild-to-moderate severity and included injection site reaction, asthenia, headache, nausea, vomiting, postural hypotension, vasodilitation, and dizziness.Adrogolide can also attenuate the ability of cocaine to induce cocaine-seeking behavior and does not itself induce cocaine-seeking behavior in a rodent model of cocaine craving and relapse. In human cocaine abusers, i.v. adrogolide reduces cocaine craving and other cocaine-induced subjective effects. The results of animal abuse liability studies indicate that adrogolide is unlikely to have abuse potential in man. Adrogolide has also been re- 305CNS Drug Reviews Vol. 7, No. 3, pp. 305-316 © 2001 Neva Press, Branford, Connecticut Address correspondence and reprint requests to: William J. Giardina, PhD, CNS Diseases Research D-4N5, AP9A, Abbott Laboratories, 100 Abbott Park Road Abbott Park, IL 60064-6125, USA. Fax: +1 (847) 937-9195; E-mail: william.j.giardina@abbott.com ported to reverse haloperidol-induced cognitive deficits in monkeys, suggesting that it may be an effective treatment for the cognitive dysfunction associated with aging and disease.Adrogolide undergoes a high hepatic "first-pass" metabolism in man after oral dosing and, as a result, has a low oral bioavailability (@4%). This limitation may potentially be circumvented by oral inhalation formulations for intrapulmonary delivery that greatly increase the bioavailability of adrogolide. As the first full dopamine D 1 receptor agonist to show efficacy in PD patients and to reduce the craving and subjective effects of cocaine in cocaine abusers, adrogolide represents an important tool in understanding the pharmacotherapeutic potential of dopamine D 1 receptor agonists.

Targeting the dopamine D1 receptor in schizophrenia: insights for cognitive dysfunction

“…These data raise the possibility that mixed dopamine agonists, that may have actions that involve D 1 receptor signaling, can enhance working memory in schizophrenia and related disorders. Further research requires the use of selective, full D 1 agonists, such as ABT-431 (Giardina and Williams 2001) which do not produce tolerance in order to ascertain the particular involvement of signaling at this receptor in cognitive performance in relationship to the level of activation in dlPFC in both patient and control populations.…”

Dopamine Receptor Signaling and Current and Future Antipsychotic Drugs

“…Both compounds have similar pharmacology and have been shown to have profound antiparkinson activity (Giardina and Williams, 2001; Haney et al, 1999; Okumu et al, 2002; Rascol et al, 1999; Rascol et al, 2001; Self et al, 2000). Both compounds have little oral bioavailability, and only DHX remains available for clinical testing (George et al, 2007; Mu et al, 2007) with a phase IIa study as a cognitive enhancer in schizophrenia currently ongoing (Slifstein et al, 2011).…”

REVIEW: New developments in the pharmacotherapy of cocaine abuse

“…One D1‐like agonist, ABT‐431 (adrogolide), was studied in cocaine abusers and showed a downward trend in subjects’ ratings of cocaine craving (Haney et al . 1999), together with side effects such as headache, nausea and dizziness that may complicate its therapeutic use (Giardina & Williams 2001). Agonists of the D2‐like dopamine receptor family, such as bromocriptine and quinpirole, seem to offer limited promises as cocaine therapeutics (Soares et al .…”