We report the first isolation of the alkaloid aaptamine from the Philippine marine sponge Stylissa sp. Aaptamine possessed weak antiproliferative activity against HCT116 colon cancer cells and inhibited the proteasome in vitro at 50 microM. These activities may be functionally linked. Due to its known, more potent activity on certain G-protein coupled receptors (GPCRs), including alpha-adrenergic and delta-opioid receptors, the compound was profiled more broadly at sub-growth inhibitory concentrations against a panel of 168 GPCRs to potentially reveal additional targets and therapeutic opportunities. GPCRs represent the largest class of drug targets. The primary screen at 20 microM using the beta-arrestin functional assay identified the antagonist, agonist, and potentiators of agonist activity of aaptamine. Dose-response analysis validated the alpha-adrenoreceptor antagonist activity of aaptamine (ADRA2C, IC(50) 11.9 microM) and revealed the even more potent antagonism of the beta-adrenoreceptor (ADRB2, IC(50) 0.20 microM) and dopamine receptor D4 (DRD4, IC(50) 6.9 microM). Additionally, aaptamine showed agonist activity on selected chemokine receptors, by itself (CXCR7, EC(50) 6.2 microM; CCR1, EC(50) 11.8 microM) or as a potentiator of agonist activity (CXCR3, EC(50) 31.8 microM; CCR3, EC(50) 16.2 microM). These GPCRs play a critical role in the treatment of cardiovascular disease, diabetes, cancer, and neurological disorders. The results of this study may thus provide novel preventive and therapeutic strategies for noncommunicable diseases (NCDs).