The pharmacological properties and therapeutic use of apomorphine

Abstract

Apomorphine (APO) is an aporphine derivative used in human and veterinary medicine. APO activates D₁, D(2S), D(2L), D₃, D₄, and D₅ receptors (and is thus classified as a non-selective dopamine agonist), serotonin receptors (5HT(1A), 5HT(2A), 5HT(2B), and 5HT(2C)), and α-adrenergic receptors (α(1B), α(1D), α(2A), α(2B), and α(2C)). In veterinary medicine, APO is used to induce vomiting in dogs, an important early treatment for some common orally ingested poisons (e.g., anti-freeze or insecticides). In human medicine, it has been used in a variety of treatments ranging from the treatment of addiction (i.e., to heroin, alcohol or cigarettes), for treatment of erectile dysfunction in males and hypoactive sexual desire disorder in females to the treatment of patients with Parkinson's disease (PD). Currently, APO is used in patients with advanced PD, for the treatment of persistent and disabling motor fluctuations which do not respond to levodopa or other dopamine agonists, either on its own or in combination with deep brain stimulation. Recently, a new and potentially important therapeutic role for APO in the treatment of Alzheimer's disease has been suggested; APO seems to stimulate Aβ catabolism in an animal model and cell culture, thus reducing the rate of Aβ oligomerisation and consequent neural cell death.

Figure 1

Activity of the major connections in the basal ganglia in patients with PD after APO medication (left); in untreated PD patients (center) and in healthy subjects (right) [10,18]. The green lines denote excitatory pathways; the red lines denote inhibitory pathways. A thick line denotes increased activity and a dotted line denotes a decreased activity. APO (apomorphine); D₂, D₁ (D₁ and D₂-like dopaminergic receptors); Gpe (external segment of globus pallidus); Gpi (internal segment of globus pallidus); Snc (compact segment of substantia nigra); SNr (reticular segment of substantia nigra); STN (subthalamic nucleus).

Figure 2

Central pathways controlling erection and ejaculation [36,42,43]. AN (accumbens nucleus); APO (apomorphine); MPAN (medial preoptic area nucleus); PFC (prefrontal cortex);PVN (paraventricular nucleus); + (accentuated activity); − (attenuated activity). Central dopaminergic neurons form synapses in the PVN and MPAN and dopaminergic neurons project from the hypothalamus to the spinal cord. APO promotes erection by acting mainly on the D₂-like receptors in the central nervous system. The effect of APO on erection and ejaculation is shown with bold (+) or (−) symbols.

Figure 3

The non-amyloidogenic and amyloidogenic metabolic pathways of amyloid precursor protein (APP) [6,59,66,89,90,91,93,94,97,98,99,100,101]. APO (apomorphine); SAPPα (soluble peptide APPα); SAPP_β (soluble peptide APP_β); Aβ (Aβ42 peptide); α-S (α-secretase); β-S (β-secretase); γ-S (γ-secretase); CTF-83 and CTF-99 (83 and 99-amino acid membrane bound C-terminal fragment), NFT (neurofibrillary tangles); APP-ICD (APP intracellular domain); ROS (reactive oxygen species); + (accentuated activity); − (attenuated activity). The effect of APO is shown with bold (+) or (−) symbols.