Approximately 30% of the drugs on the market exert their biological activities upon binding to G-protein Coupled Receptors (GPCRs). As biological targets, GPCRs are associated with exceptional progress in the field of drug research, enabling the application of molecular strategies for the discovery of innovative therapeutic principles. However, a short coming of this class of drugs that bind to the orthosteric site allows for many potential adverse side effects by also targeting other closely related receptor subtypes and other off- target sits. A new class of drugs called allosteric modulators are rapidly being developed in the pharmaceutical industry that limit these shortcomings by binding to unique sites on the receptor separate from the orthosteric site and have no activity on their own. Positive allosteric modulators (PAMs) enhance endogenous ligand activity through either augmenting efficacy or potency and only when the endogenous ligand is bound to the receptor. So an “off” receptor stays off even if the PAM is circulating in the body. While Alzheimer’s Disease (AD) is characterized by neuritic plaques and neurofibrillary tangles, composed mostly of b-amyloid and tau, clinical trials focused on amyloid immunotherapies have been disappointing. Loss of neuronal synaptic density is another invariant feature of the disease that appears to precede neuronal loss and this is where agents targeted to enhance neurogenesis, long term potentiation, and synaptic plasticity in cognitive areas may benefit AD patients and may provide an alternative method of treatment, particularly in light of the disappointing immunotherapies. The α1A-adrenergic receptor (AR) subtype is a GPCR together with two-other closely related subtypes (a1B, a1D) plus six other more distantly-related subtypes (b1, b2, b3, a2A, a2B, a2C). We have previously shown in vivo and in vitro that the α1A-AR subtype is expressed in key cognitive centers of the brain, is both cardiac and neuroprotective, and activation of this receptor can increase cognition, synaptic plasticity, long term potentiation, and adult neurogenesis in normal WT mice. We have developed a novel small molecular weight compound that is orally bioactive and is a PAM of the a1A-AR. It is selective for the norepinephrine-bound receptor only and has no effect on the epinephrine-bound receptor. This PAM is not an agonist and does not invoke signaling on its own. However, it potentiates the NE-mediated cAMP response which is responsible for the cognitive benefits of NE in the brain with no effects on the inositol phosphate response which mediates peripheral cardiovascular effects, and particularly increased blood pressure. We have performed a 10 month dosing study with this PAM in vivo in the 3xTG AD mouse model and showed statistically increased long term potentiation, synaptic plasticity, and cognitive improvement with no apparent toxicity and no increase in blood pressure. Our objective is to further derivatize our lead...