RESUMO
Clinical development of catechol-based orthosteric agonists of the dopamine D1 receptor has thus far been unsuccessful due to multiple challenges. To address these issues, we identified LY3154207 (3) as a novel, potent, and subtype selective human D1 positive allosteric modulator (PAM) with minimal allosteric agonist activity. Conformational studies showed LY3154207 adopts an unusual boat conformation, and a binding pose with the human D1 receptor was proposed based on this observation. In contrast to orthosteric agonists, LY3154207 showed a distinct pharmacological profile without a bell-shaped dose-response relationship or tachyphylaxis in preclinical models. Identification of a crystalline form of free LY3154207 from the discovery lots was not successful. Instead, a novel cocrystal form with superior solubility was discovered and determined to be suitable for development. This cocrystal form was advanced to clinical development as a potential first-in-class D1 PAM and is now in phase 2 studies for Lewy body dementia.
Assuntos
Isoquinolinas/farmacologia , Receptores de Dopamina D1/agonistas , Acetilcolina/metabolismo , Administração Oral , Regulação Alostérica/efeitos dos fármacos , Animais , Sítios de Ligação , Cristalografia por Raios X , AMP Cíclico/metabolismo , Células HEK293 , Meia-Vida , Humanos , Isoquinolinas/química , Isoquinolinas/farmacocinética , Rim/efeitos dos fármacos , Rim/metabolismo , Locomoção/efeitos dos fármacos , Camundongos , Conformação Molecular , Isoformas de Proteínas/agonistas , Isoformas de Proteínas/metabolismo , Ratos , Receptores de Dopamina D1/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-AtividadeRESUMO
In the present study, the role of 5-HT(1A) receptors in control of lower urinary tract function in cats was examined using 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) as agonists and WAY100635 and LY206130 as antagonists. Bladder function was assessed using cystometric infusion of saline or 0.5% acetic acid to produce bladder irritation. External urethral sphincter (EUS) function was assessed using electromyographic (EMG) recordings of activity recorded during cystometry or by recording electrically evoked pudendal reflexes. Both 5-HT(1A) receptor agonists caused dose-dependent decreases in bladder activity and increases in EUS EMG activity under conditions of acetic acid infusion. 5-HT(1A) receptor antagonists reversed both the bladder-inhibitory and sphincter-facilitatory effects. Thus, 5-HT(1A) receptor activation can have opposite effects on nociceptive afferent processing depending upon the efferent response being measured. During saline infusion of the bladder, 8-OH-DPAT produced moderate inhibition of bladder activity and had no significant effect on sphincter electromyographic (EMG) activity. 8-OH-DPAT either had no effect, or inhibited, low-threshold electrically evoked pudendal reflexes. These findings indicate that 5-HT(1A) receptor stimulation is inhibitory to bladder function in cats, especially under conditions where the bladder is hyperactive due to irritation. Furthermore, these bladder-inhibitory effects are the exact opposite of the bladder-excitatory effects of 8-OH-DPAT reported in rats. 5-HT(1A) receptor stimulation increases EUS motoneuron activity when driven by nociceptive bladder afferent inputs but not when driven by non-nociceptive afferent inputs. In summary, 5-HT(1A) receptor agonists facilitate a nociceptor-driven spinal reflex (sphincter activity) but inhibit a nociceptor-driven supraspinal reflex (micturition). This pattern of activity would facilitate urine storage and may be important under 'fight-or-flight' conditions when serotonergic activity is high.